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Peak voltage is not action potential amplitude; amplitude equals peak minus resting potential.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 037 · Honda 2011 · Diltiazem","additional_evidence":[],"supporting_assessment":{}},{"number":38,"display_number":38,"drug":"Dofetilide","classification":"main_effect","source_name":"Barral 2025","source_url":"https://doi.org/10.1371/journal.pcbi.1012913","dose_basis":"nominal; Table 2 says concentration was not bioanalytically measured","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":0.001,"median":273.941724392287,"delta":3.87383318331985,"delta_percent":1.4542130461985,"q25":3.6337794169437503,"q75":4.111320627666503,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.983625939612924,"qnet_absolute":0.0590329586689402,"peak_voltage":40.705021971116},{"dose":0.01,"median":314.400679997156,"delta":43.6040402685485,"delta_percent":16.2819858080564,"q25":40.891669688933206,"q75":46.34077260881763,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.823152676492252,"qnet_absolute":0.0492799934398579,"peak_voltage":40.8859789911246},{"dose":0.1,"median":525.928321714541,"delta":258.204193812136,"delta_percent":98.506407751899,"q25":236.13145334163198,"q75":284.91133763374,"n":487,"paired_n":487,"cells":500,"ead":13,"dad":3,"late_flip":16,"overlap":13,"qnet_relative":0.201171201756564,"qnet_absolute":0.011950584922066,"peak_voltage":41.730039949708},{"dose":0.2,"median":588.208947986301,"delta":338.343890940227,"delta_percent":133.776694234695,"q25":298.8489150319665,"q75":374.601757005558,"n":439,"paired_n":439,"cells":500,"ead":60,"dad":23,"late_flip":83,"overlap":61,"qnet_relative":0.0769495776357674,"qnet_absolute":0.00402563192078788,"peak_voltage":41.302975470982}],"observed":"APD90 prolongation","predicted":"APD90 prolongation","observed_points":[{"dose":0.001,"mean":20,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.01,"mean":82,"sem":8,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.1,"mean":256,"sem":21,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.2,"mean":318,"sem":33,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"}],"observed_unit":"ms","observed_endpoint":"Observed APD90 change (ms)","comparison_note":"Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 439/500 valid cells and excludes unavailable crossings. Source APD analysis excluded one trabecula with EAD at 0.1 uM. Numerical agreement and clinical safety are not asserted.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 038 · Barral 2025 · Dofetilide","additional_evidence":[],"supporting_assessment":{}},{"number":39,"display_number":39,"drug":"Dofetilide","classification":"main_effect","source_name":"Barral 2025","source_url":"https://doi.org/10.1371/journal.pcbi.1012913","dose_basis":"nominal; Table 2 says concentration was not bioanalytically measured","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":0.001,"median":272.693743795489,"delta":2.64131311610765,"delta_percent":0.991269765195785,"q25":2.476461955167345,"q75":2.80110238988534,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.988829579308779,"qnet_absolute":0.059292705531475,"peak_voltage":40.6951625671235},{"dose":0.01,"median":305.782167246014,"delta":35.5832757830981,"delta_percent":13.310969370841,"q25":33.42072091780925,"q75":37.85954221945855,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.854722977803168,"qnet_absolute":0.0510681891389526,"peak_voltage":40.8584257727721},{"dose":0.1,"median":518.827693636751,"delta":250.099890201283,"delta_percent":95.2756244896988,"q25":228.803574917693,"q75":275.092638984857,"n":489,"paired_n":489,"cells":500,"ead":11,"dad":3,"late_flip":14,"overlap":11,"qnet_relative":0.216329021075183,"qnet_absolute":0.0129365075614979,"peak_voltage":41.664602041884},{"dose":0.2,"median":587.294381112032,"delta":336.83917043054,"delta_percent":132.850478208631,"q25":299.01362028411603,"q75":373.98315485708747,"n":438,"paired_n":438,"cells":500,"ead":60,"dad":20,"late_flip":80,"overlap":62,"qnet_relative":0.0800981555329797,"qnet_absolute":0.00411106186934051,"peak_voltage":41.3040721987291}],"observed":"APD90 prolongation","predicted":"APD90 prolongation","observed_points":[{"dose":0.001,"mean":20,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.01,"mean":82,"sem":8,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.1,"mean":256,"sem":21,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":0.2,"mean":318,"sem":33,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"}],"observed_unit":"ms","observed_endpoint":"Observed APD90 change (ms)","comparison_note":"Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 438/500 valid cells and excludes unavailable crossings. Source APD analysis excluded one trabecula with EAD at 0.1 uM. Numerical agreement and clinical safety are not asserted.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 039 · Barral 2025 · Dofetilide","additional_evidence":[],"supporting_assessment":{}},{"number":40,"display_number":40,"drug":"Quinidine","classification":"main_effect","source_name":"Barral 2025","source_url":"https://doi.org/10.1371/journal.pcbi.1012913","dose_basis":"nominal; Table 2 says concentration was not bioanalytically measured","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":0.1,"median":284.151542055705,"delta":13.4832941450906,"delta_percent":5.03103383607839,"q25":12.643379214003525,"q75":14.483323351230474,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.950476000409054,"qnet_absolute":0.0571079258951089,"peak_voltage":40.5840936113026},{"dose":1,"median":379.572586413653,"delta":109.121899001989,"delta_percent":40.2289107566685,"q25":101.4432171079255,"q75":116.26302270875875,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.632738654299673,"qnet_absolute":0.0372454406613038,"peak_voltage":40.5291566387239},{"dose":10,"median":602.286783614496,"delta":338.684143912065,"delta_percent":131.087665518252,"q25":304.486558239705,"q75":379.2885546552265,"n":487,"paired_n":487,"cells":500,"ead":12,"dad":3,"late_flip":15,"overlap":13,"qnet_relative":0.204117714811032,"qnet_absolute":0.0124198509505315,"peak_voltage":39.3773563958885}],"observed":"APD90 prolongation","predicted":"APD90 prolongation","observed_points":[{"dose":0.1,"mean":6,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":1,"mean":8,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":10,"mean":37,"sem":7,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"}],"observed_unit":"ms","observed_endpoint":"Observed APD90 change (ms)","comparison_note":"Table 1 contains measured adult-human ex vivo APD90, not published simulations. 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Only IKr and ICaL potency are represented; neutral effects on other channels are assumptions.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 040 · Barral 2025 · Quinidine","additional_evidence":[],"supporting_assessment":{}},{"number":41,"display_number":41,"drug":"Quinidine","classification":"main_effect","source_name":"Barral 2025","source_url":"https://doi.org/10.1371/journal.pcbi.1012913","dose_basis":"nominal; Table 2 says concentration was not bioanalytically measured","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":0.1,"median":276.974910472316,"delta":6.85505596094163,"delta_percent":2.56223698106019,"q25":6.408752297271057,"q75":7.325617763184162,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.974071781841555,"qnet_absolute":0.0584619173886129,"peak_voltage":40.6466689519671},{"dose":1,"median":402.453895322521,"delta":131.348649169117,"delta_percent":48.5302781609928,"q25":122.062608298653,"q75":140.27083976762026,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.566176583625023,"qnet_absolute":0.0335497753593071,"peak_voltage":40.6107749091896},{"dose":10,"median":658.797450443403,"delta":396.335326215648,"delta_percent":150.765741254518,"q25":348.6425849669855,"q75":442.6525598939403,"n":484,"paired_n":484,"cells":500,"ead":5,"dad":3,"late_flip":8,"overlap":16,"qnet_relative":0.159859140865737,"qnet_absolute":0.00994850461782443,"peak_voltage":38.2189726527515}],"observed":"APD90 prolongation","predicted":"APD90 prolongation","observed_points":[{"dose":0.1,"mean":6,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":1,"mean":8,"sem":5,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"},{"dose":10,"mean":37,"sem":7,"n":null,"system":"adult human ventricular trabeculae","endpoint":"APD90 change from baseline","source":"Barral 2025","url":"https://doi.org/10.1371/journal.pcbi.1012913"}],"observed_unit":"ms","observed_endpoint":"Observed APD90 change (ms)","comparison_note":"Table 1 contains measured adult-human ex vivo APD90, not published simulations. 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Only IKr and ICaL potency are represented; neutral effects on other channels are assumptions.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 041 · Barral 2025 · Quinidine","additional_evidence":[],"supporting_assessment":{}},{"number":42,"display_number":42,"drug":"Alfuzosin","classification":"main_effect","source_name":"Cardiac tissue 2022","source_url":"https://www.nature.com/articles/s41598-022-17498-0","dose_basis":"Exactly0.3uM tested in primary human cardiac tissue FPD study and rabbit repolarization study. 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The sodium-enhancement mechanism is absent from the inhibition-only model inputs.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":null,"study":"Study 042 · Cardiac tissue 2022 · Alfuzosin","additional_evidence":[],"supporting_assessment":{}},{"number":43,"display_number":43,"drug":"Lacosamide","classification":"main_effect","source_name":"Wolfes 2025","source_url":"https://doi.org/10.3390/ph18050726","dose_basis":"Exactly10and50uM in Wolfes2025 native rabbit-heart arm. 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Liu2020 used chronic 24 h hiPSC exposure and mouse hearts; chronic ROS/protein-loss/calcium-channel activation mechanisms and clinical TdP are not reproduced by static inhibition.","agreement_scope":"Qualitative APD prolongation; EADs supported by separate mouse-heart observations"}},{"number":101,"display_number":97,"drug":"Toremifene","classification":"context_only","source_name":"Oxford_Zhou2020_I","source_url":"https://doi.org/10.3389/fphar.2019.01643","dose_basis":"Exploratory1/2/3/4times published clinical free Cmax; not concentrations matched to a measured cellular experimental dose-response.","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":0.0263,"median":271.010951230547,"delta":0.947226935032717,"delta_percent":0.355566113747241,"q25":0.8881047055909616,"q75":1.0048073308233576,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.995991098655771,"qnet_absolute":0.0597320300428996,"peak_voltage":40.6815737507793},{"dose":0.0526,"median":271.957589595815,"delta":1.88940492272724,"delta_percent":0.709053458623149,"q25":1.7718578237828724,"q75":2.0040351102688376,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.992010363526838,"qnet_absolute":0.0594852095947446,"peak_voltage":40.6891436142649},{"dose":0.0789,"median":272.87544867313,"delta":2.82652570135136,"delta_percent":1.06080140754903,"q25":2.650422903176935,"q75":2.9979906220706147,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.988052115832029,"qnet_absolute":0.0592552866567028,"peak_voltage":40.696667260969},{"dose":0.1052,"median":273.823166340615,"delta":3.75750532345793,"delta_percent":1.41056051557613,"q25":3.5247361769291374,"q75":3.9878538947590125,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.984115515796914,"qnet_absolute":0.059059634500295,"peak_voltage":40.7041123451368}],"observed":"Historical clinical risk context","predicted":"APD90 prolongation","observed_points":[],"observed_unit":"ms","observed_endpoint":"Observed duration change","comparison_note":"Exploratory 1–4× published free Cmax. Historical clinical risk labels are not measured APD changes at these doses.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":"TdP risk positive","study":"Study 101 · Oxford_Zhou2020_I · Toremifene","additional_evidence":[],"supporting_assessment":{}},{"number":102,"display_number":98,"drug":"Voriconazole","classification":"context_only","source_name":"Oxford_Passini2017","source_url":"https://doi.org/10.3389/fphys.2017.00668","dose_basis":"Exploratory1/2/3/4times published clinical free Cmax; not concentrations matched to a measured cellular experimental dose-response.","model":[{"dose":0,"median":270.059215049433,"delta":0.0,"delta_percent":0.0,"q25":0.0,"q75":0.0,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":1.0,"qnet_absolute":0.0599804995066363,"peak_voltage":40.6740189300485},{"dose":7.563,"median":271.497497360864,"delta":1.51104378166224,"delta_percent":0.54899617231696,"q25":1.3524580380680524,"q75":1.7363860730576601,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.995576635795627,"qnet_absolute":0.0596685423190768,"peak_voltage":40.5537212765161},{"dose":15.126,"median":273.171542677944,"delta":3.00934691728673,"delta_percent":1.09596165918443,"q25":2.7003780800387074,"q75":3.4538910309943125,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.991207128040448,"qnet_absolute":0.0593605969714658,"peak_voltage":40.432456444786},{"dose":22.689,"median":274.77453339012,"delta":4.49657805437229,"delta_percent":1.6370732154587,"q25":4.030042240125993,"q75":5.166075137358533,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.986907005449211,"qnet_absolute":0.0590558174489237,"peak_voltage":40.307257247439},{"dose":30.252,"median":276.28184154218,"delta":5.9793756458776,"delta_percent":2.17517868766733,"q25":5.35524670775107,"q75":6.873908390803612,"n":500,"paired_n":500,"cells":500,"ead":0,"dad":0,"late_flip":0,"overlap":0,"qnet_relative":0.982619512759569,"qnet_absolute":0.0587556052853464,"peak_voltage":40.1835586615504}],"observed":"Historical clinical risk context","predicted":"APD90 prolongation","observed_points":[],"observed_unit":"ms","observed_endpoint":"Observed duration change","comparison_note":"Exploratory 1–4× published free Cmax. Historical clinical risk labels are not measured APD changes at these doses.","protocol":{"cells":500,"beats":10,"cycle_ms":1000},"historical_label":"Conditional TdP risk","study":"Study 102 · Oxford_Passini2017 · Voriconazole","additional_evidence":[],"supporting_assessment":{}}],"full_review":{"counts":{"full":59,"partial":20,"not_predicted":9},"agreement":79,"agreement_percent":89.77272727272727,"criterion":"Capture the qualitative effect direction or presence at an active modeled concentration. Exact quantitative equality and exact concentration coincidence are not required. Mixed or incomplete endpoint agreement is partial.","scope_limits":["All 88 displayed compounds have completed source reviews; 98 stored study runs are consolidated without averaging.","The displayed comparison set contains compounds with interpretable measured outcome evidence.","Cellular APD, whole-heart QT, clinical QTc and calcium-transient endpoints remain labeled separately.","Clinical associations and case reports retain their combination, disease and mechanistic limitations.","A descriptive model change smaller than 1 ms at every dose is labeled Minimal APD90 change; this is not a statistical or clinical safety cutoff.","No measured curve, experimental reference point, SEM, oral-dose conversion or clinical TdP observation is invented.","This retrospective qualitative comparison is not a measure of clinical predictive accuracy."],"reviewed_compounds":88,"completed_study_runs":98,"records":[{"number":1,"display_number":1,"drug":"Astemizole","studies":[1,32],"grade":"full","observed":"AP prolongation; EAD-like events","predicted":"APD90 prolongation; EAD detected","reason":"The audited model output captures the reported ap prolongation; ead-like events.","limitations":"Higher experimental doses have unavailable durations because of events; agreement uses eligible observations. EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":2,"display_number":2,"drug":"Azimilide","studies":[2],"grade":"full","observed":"Shift towards AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported shift towards ap prolongation.","limitations":"Low-dose response differs between cell lines; higher optical durations are frequently unavailable.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Shift towards AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":3,"display_number":3,"drug":"Bepridil","studies":[3],"grade":"full","observed":"AP prolongation; heterogeneous response","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation; heterogeneous response.","limitations":"Dose response is heterogeneous; source high-dose quiescence is not a complete matched phenotype.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation; heterogeneous response","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":4,"display_number":4,"drug":"Chlorpromazine","studies":[4],"grade":"full","observed":"AP prolongation in some assay series","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation in some assay series.","limitations":"Prolongation was significant in only some laboratory datasets; the result does not describe every site.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation in some assay series","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":5,"display_number":5,"drug":"Cisapride","studies":[5],"grade":"full","observed":"AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation.","limitations":"High-dose events limit experimental duration measurements.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":6,"display_number":6,"drug":"Clarithromycin","studies":[6],"grade":"partial","observed":"Initial shortening, then prolongation","predicted":"APD90 prolongation","reason":"Later prolongation captured; initial shortening missed.","limitations":"Initial shortening was not reproduced, although the high-dose prolonging effect agrees.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Initial shortening, then prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":7,"display_number":7,"drug":"Clozapine","studies":[7],"grade":"full","observed":"Shift towards AP prolongation; variable response","predicted":"APD90 prolongation","reason":"The audited model output captures the reported shift towards ap prolongation; variable response.","limitations":"Experimental responses vary between sites and cell lines; the result concerns the main prolonging trend.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Shift towards AP prolongation; variable response","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":8,"display_number":8,"drug":"Diltiazem","studies":[8,37],"grade":"partial","observed":"AP shortening","predicted":"Mixed APD90 response","reason":"Shortening through 1 µM captured; direction reverses incorrectly at 10 µM.","limitations":"Shortening agrees through 1 µM; at 10 µM the model changes towards prolongation. Direction agrees at both source-matched nominal doses; magnitude differs. Honda used immature hiPS cells at room temperature and 0.1 Hz, versus adult ORd at 1 Hz and ten fast cycles. Potency is independently sourced from Li 2019. Peak voltage is not action potential amplitude; amplitude equals peak minus resting potential.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1254/jphs.11038FP","title":"Honda 2011","endpoint":"Observed APD90 change (%)","system":"201B7 hiPS-CM ventricular-like single cells","exposure":"applied bath concentration","claim":"APD90 shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":9,"display_number":9,"drug":"Disopyramide","studies":[9],"grade":"partial","observed":"Prolongation; mixed high-dose response","predicted":"APD90 prolongation","reason":"Lower-dose prolongation captured; high-dose quiescence and mixed response are not fully reproduced.","limitations":"Lower-dose prolongation agrees; quiescence and mixed surviving-well responses limit the high-dose comparison.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Prolongation; mixed high-dose response","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":10,"display_number":10,"drug":"Dofetilide","studies":[10,29,38,39],"grade":"full","observed":"AP prolongation; EAD-like events","predicted":"APD90 prolongation; EAD detected","reason":"The audited model output captures the reported ap prolongation; ead-like events.","limitations":"Only eligible source durations are displayed; event frequency has not been quantitatively validated. EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles. Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 439/500 valid cells and excludes unavailable crossings. Source APD analysis excluded one trabecula with EAD at 0.1 uM. Numerical agreement and clinical safety are not asserted. Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 438/500 valid cells and excludes unavailable crossings. Source APD analysis excluded one trabecula with EAD at 0.1 uM. Numerical agreement and clinical safety are not asserted.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1371/journal.pcbi.1012913","title":"Barral 2025","endpoint":"Observed APD90 change (ms)","system":"adult human ventricular trabeculae","exposure":"nominal; Table 2 says concentration was not bioanalytically measured","claim":"APD90 prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1371/journal.pcbi.1012913","title":"Barral 2025","endpoint":"Observed APD90 change (ms)","system":"adult human ventricular trabeculae","exposure":"nominal; Table 2 says concentration was not bioanalytically measured","claim":"APD90 prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":11,"display_number":11,"drug":"Domperidone","studies":[11],"grade":"full","observed":"Dose-related AP prolongation","predicted":"Mixed APD90 response","reason":"The audited model output captures the reported dose-related ap prolongation.","limitations":"Small low-dose changes differ, while the main shift towards prolongation agrees.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Dose-related AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":12,"display_number":12,"drug":"Droperidol","studies":[12],"grade":"full","observed":"AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation.","limitations":"High-dose experimental durations are often unavailable.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":13,"display_number":13,"drug":"Ibutilide","studies":[13],"grade":"full","observed":"AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation.","limitations":"Experimental events limit higher-dose duration measurements.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":14,"display_number":14,"drug":"Loratadine","studies":[14],"grade":"partial","observed":"APD90c shortening / no marked prolongation; non-monotonic dose response","predicted":"APD90 shortening","reason":"Shortening relative to control and absence of prolongation are captured. All eight published site-2 cell-line means are negative, but the observed profile is non-monotonic and does not follow the model's progressively greater shortening. The earlier inconclusive label described the dose gradient, not missing simulation data.","limitations":"Only the relative-to-control shortening / lack of prolongation is aligned. A monotonic experimental concentration response is not established. Clinical QTc provides separate context and is not substituted for cellular APD90c. No oral-dose to bath-concentration conversion is made.","label":"Relevant Effect Captured","detail":"Partial agreement","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova et al. 2018 · International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment","endpoint":"Baseline- and vehicle-controlled, rate-corrected APD90 (ddAPD90c)","system":"VSO site 2; Cor.4U and iCell2 hiPSC cardiomyocytes","exposure":"0.00095, 0.003, 0.00949 and 0.03 µM","claim":"All eight selected cell-line/dose means show shortening relative to baseline and vehicle, with a non-monotonic concentration profile and source-supplied SEM/n.","locator":"Raw multisite supplemental workbook; Drug_Name=Loratadine, site=2, Platform=CLY (optical VSO); Supplemental Table 2 nominal doses. Existing 20261010 numeric QA verified all selected rows."},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2015013/","title":"Kosoglou et al. 2000 · Pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with ketoconazole or cimetidine","endpoint":"Clinical QTc","system":"Healthy volunteers; randomized crossover","exposure":"10 mg loratadine daily for 10 days, alone or with metabolic inhibitors","claim":"No significant QTc prolongation despite increased plasma exposure during coadministration.","locator":"Abstract Results and Conclusions; electrocardiographic evaluation"}]},{"number":15,"display_number":15,"drug":"Metoprolol","studies":[15],"grade":"full","observed":"AP prolongation at high concentrations","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation at high concentrations.","limitations":"This is a high-dose cellular effect; clinical beta-blockade is not modelled.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation at high concentrations","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":16,"display_number":16,"drug":"Mexiletine","studies":[16],"grade":"partial","observed":"AP shortening; high-dose quiescence","predicted":"APD90 shortening","reason":"Initial shortening captured; later response and quiescence are not fully reproduced.","limitations":"Initial shortening agrees; the full high-dose profile and source quiescence are not reproduced.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP shortening; high-dose quiescence","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":17,"display_number":17,"drug":"Nifedipine","studies":[17],"grade":"full","observed":"AP shortening","predicted":"APD90 shortening","reason":"The audited model output captures the reported ap shortening.","limitations":"Direction agrees; magnitudes and high-dose quiescence differ.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":18,"display_number":18,"drug":"Nitrendipine","studies":[18],"grade":"full","observed":"AP shortening","predicted":"APD90 shortening","reason":"The audited model output captures the reported ap shortening.","limitations":"Shortening agrees; one high-dose optical series has only one eligible observation.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":19,"display_number":19,"drug":"Ondansetron","studies":[19],"grade":"full","observed":"AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation.","limitations":"Higher optical durations are unavailable; agreement uses eligible lower-dose observations.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":20,"display_number":20,"drug":"Pimozide","studies":[20,35],"grade":"partial","observed":"Shift towards AP prolongation; EAD-like events","predicted":"APD90 prolongation; EAD not observed","reason":"Prolongation captured; EADs were absent at all modeled active doses.","limitations":"One cell line has an initial negative change; the later shift towards prolongation agrees. EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Shift towards AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":21,"display_number":21,"drug":"Quinidine","studies":[21,30,40,41],"grade":"full","observed":"AP prolongation and arrhythmic events; EAD-like events","predicted":"APD90 prolongation; EAD detected","reason":"The audited model output captures the reported ap prolongation and arrhythmic events; ead-like events.","limitations":"Preferred optical APD has one eligible dose at 0.95 µM; separate MEA evidence supports the general prolonging effect. EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles. Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 487/500 valid cells and excludes unavailable crossings. Positive dose trend agrees, but magnitude is strongly overpredicted (338.7 ms versus 37 ± 7 ms). This does not validate quantitative APD, combined-block mitigation or clinical safety. Only IKr and ICaL potency are represented; neutral effects on other channels are assumptions. Table 1 contains measured adult-human ex vivo APD90, not published simulations. Pharm and CiPA vary channel inputs against the same experiment; they are not independent validations. Ten cycles differ from the published model’s 1500 prepaces; extracellular ions also differ. Highest-dose APD90 median includes 484/500 valid cells and excludes unavailable crossings. Positive dose trend agrees, but magnitude is strongly overpredicted (396.3 ms versus 37 ± 7 ms). This does not validate quantitative APD, combined-block mitigation or clinical safety. Only IKr and ICaL potency are represented; neutral effects on other channels are assumptions.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation and arrhythmic events","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1371/journal.pcbi.1012913","title":"Barral 2025","endpoint":"Observed APD90 change (ms)","system":"adult human ventricular trabeculae","exposure":"nominal; Table 2 says concentration was not bioanalytically measured","claim":"APD90 prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1371/journal.pcbi.1012913","title":"Barral 2025","endpoint":"Observed APD90 change (ms)","system":"adult human ventricular trabeculae","exposure":"nominal; Table 2 says concentration was not bioanalytically measured","claim":"APD90 prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":22,"display_number":22,"drug":"Ranolazine","studies":[22],"grade":"full","observed":"Dose-related AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported dose-related ap prolongation.","limitations":"Low-dose optical responses vary; cellular events are not equivalent to clinical TdP.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Dose-related AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":23,"display_number":23,"drug":"Risperidone","studies":[23],"grade":"full","observed":"Shift towards AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported shift towards ap prolongation.","limitations":"Both optical lines move towards prolongation; low-dose responses and other assay platforms vary.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Shift towards AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":24,"display_number":24,"drug":"Sotalol","studies":[24,31],"grade":"partial","observed":"AP prolongation; EAD-like events","predicted":"APD90 prolongation; EAD not observed","reason":"Prolongation captured; EADs were absent at all modeled active doses.","limitations":"The APD direction agrees; the separately assessed EAD-like effect remains absent in tested simulations. EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"},{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":25,"display_number":25,"drug":"Tamoxifen","studies":[25],"grade":"not_predicted","observed":"Shortening in iCell; assay-dependent response","predicted":"APD90 prolongation","reason":"The reported effect is not reproduced by the tested model outputs: APD90 prolongation.","limitations":"iCell observations predominantly shorten; some other assay series prolong. The model prolongs throughout.","label":"Effect Not Captured","detail":"At tested model exposures","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Shortening in iCell; assay-dependent response","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":26,"display_number":26,"drug":"Terfenadine","studies":[26],"grade":"partial","observed":"Initial shortening, then prolongation","predicted":"APD90 prolongation","reason":"Later prolongation and an EAD flag captured; initial shortening and high-dose quiescence are not fully reproduced.","limitations":"Source low-dose shortening is missed; subsequent prolongation agrees. The highest source dose becomes quiescent.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"Initial shortening, then prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":27,"display_number":27,"drug":"Vandetanib","studies":[27],"grade":"full","observed":"AP prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported ap prolongation.","limitations":"Main prolongation agrees; high-dose events limit eligible duration observations.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":28,"display_number":28,"drug":"Verapamil","studies":[28],"grade":"not_predicted","observed":"AP shortening","predicted":"APD90 prolongation","reason":"The reported effect is not reproduced by the tested model outputs: APD90 prolongation.","limitations":"The experimental shortening trend contrasts with increasing model APD90.","label":"Effect Not Captured","detail":"At tested model exposures","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1016/j.celrep.2018.08.079","title":"Blinova 2018","endpoint":"Observed ddAPD90c (ms)","system":"Cor.4U; iCell2","exposure":"Original Supplemental Table2 nominal bath concentrations, not free Cmax multiples. Base1uM is an exact unit conversion for importing the nominal concentrations as multipliers.","claim":"AP shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":29,"display_number":29,"drug":"Sertindole","studies":[33],"grade":"full","observed":"Published EAD-like event","predicted":"EAD flags detected","reason":"The audited model output captures the reported published ead-like event.","limitations":"EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":30,"display_number":30,"drug":"Erythromycin","studies":[34],"grade":"not_predicted","observed":"Published EAD-like event","predicted":"EAD not observed at tested doses","reason":"The reported effect is not reproduced by the tested model outputs: EAD not observed at tested doses.","limitations":"EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Effect Not Captured","detail":"At tested model exposures","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":31,"display_number":31,"drug":"Sparfloxacin","studies":[36],"grade":"not_predicted","observed":"Published EAD-like event","predicted":"EAD not observed at tested doses","reason":"The reported effect is not reproduced by the tested model outputs: EAD not observed at tested doses.","limitations":"EAD comparison uses presence at any tested concentration of the same molecule. Experimental one-hour observation differs from ten paced simulation cycles.","label":"Effect Not Captured","detail":"At tested model exposures","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1093/toxsci/kfy239","title":"Huo 2019","endpoint":"EAD-like event presence","system":"Preparation described in the linked primary article","exposure":"Source Table1 MEC-EAD: actual tested event-positive nominal concentration. Not IC50 or clinical free Cmax.","claim":"Published EAD-like event","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":32,"display_number":32,"drug":"Alfuzosin","studies":[42],"grade":"full","observed":"FPD/APD60/QT prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported fpd/apd60/qt prolongation.","limitations":"FPD/APD60/QT and APD90 are different endpoints. The sodium-enhancement mechanism is absent from the inhibition-only model inputs.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://www.nature.com/articles/s41598-022-17498-0","title":"Cardiac tissue 2022","endpoint":"Observed FPD change (%)","system":"Vascularised human cardiac tissue","exposure":"Exactly0.3uM tested in primary human cardiac tissue FPD study and rabbit repolarization study. Do not substitute an invented Cmax.","claim":"FPD/APD60/QT prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":33,"display_number":33,"drug":"Lacosamide","studies":[43],"grade":"full","observed":"APD90 shortening","predicted":"APD90 shortening","reason":"The audited model output captures the reported apd90 shortening.","limitations":"Rabbit APD90 means are compared with adult-human ORd; marginal SD does not establish uncertainty of paired changes.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.3390/ph18050726","title":"Wolfes 2025","endpoint":"Observed APD90 change (ms)","system":"Isolated rabbit whole-heart Langendorff, native perfusion, no sotalol","exposure":"Exactly10and50uM in Wolfes2025 native rabbit-heart arm. Both finite reported concentrations; no Cmax required.","claim":"APD90 shortening","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":34,"display_number":34,"drug":"BaCl2","studies":[44],"grade":"full","observed":"APD90 prolongation","predicted":"APD90 prolongation","reason":"The audited model output captures the reported apd90 prolongation.","limitations":"One measured concentration supports the direction; it does not establish a dose-response curve.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"original_comparison","sources":[{"url":"https://doi.org/10.1113/jphysiol.2013.261198","title":"Jost 2013","endpoint":"Observed APD90 change (%)","system":"Adult human papillary muscle","exposure":"10uM is the measured BaCl2 bath concentration in the source adult-human-tissue experiment. Base1uM is only an import unit conversion; no therapeutic Cmax is claimed.","claim":"APD90 prolongation","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":35,"display_number":35,"drug":"JNJ303","studies":[45],"grade":"partial","observed":"Small or preparation-dependent repolarisation effect","predicted":"APD80 prolongation","reason":"Positive APD80 point estimate captured; source p = 0.47 and FPD response depend on preparation.","limitations":"APD80, not APD90, is plotted. The human-wedge increase is non-significant (p = 0.47); the 2 µM FPD response depends on cell line.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"original_comparison","sources":[{"url":"https://www.nature.com/articles/s41598-017-16218-3","title":"Kang 2017 / Europace","endpoint":"Observed APD80 change (ms)","system":"Adult human LV wedge","exposure":"Two independently published nominal bath concentrations. Observations retain separate assay and cell-system identities; no pooling or clinical-Cmax substitution.","claim":"Small or preparation-dependent repolarisation effect","locator":"Source-derived observation records and per-study source notes in the audited original comparison"}]},{"number":36,"display_number":36,"drug":"Ajmaline","studies":[46],"grade":"partial","observed":"Native ventricular APD prolongation; donor hiPSC responses differ","predicted":"APD90 prolongation","reason":"CARDIX reproduces native ventricular prolongation. Donor hiPSC cells showed slight APD90 shortening in another preparation; agreement is therefore qualified. Model EAD flags are not independently validated.","limitations":"Native guinea-pig and donor/patient hiPSC preparations differ from the ORd population. Exposure and endpoint are not matched; suspected EAD is not confirmed TdP.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://www.jstage.jst.go.jp/article/ihj1960/36/4/36_4_465/_article","title":"Effects of Ajmaline on Non-sodium Ionic Currents in Guinea Pig Ventricular Myocytes (Enomoto et al., 1995)","endpoint":"APD","system":"Isolated guinea-pig ventricular myocytes","exposure":"Concentration-dependent application; exact APD dose series not transcribed","claim":"Dose-dependent APD prolongation was measured.","locator":"Abstract final result; DOI 10.1536/ihj.36.465"},{"url":"https://academic.oup.com/europace/article/21/9/1410/5491508","title":"A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes (2019)","endpoint":"APD50/APD90","system":"Healthy donor and Brugada patient hiPSC cardiomyocytes","exposure":"Sequential 3, 10 and 30 µM","claim":"Donor APD90 slightly shortened; Brugada APD slightly prolonged at 30 µM.","locator":"Results: Differential effects of ajmaline; Figure 7"}]},{"number":37,"display_number":37,"drug":"Amiodarone","studies":[47],"grade":"full","observed":"Human ventricular APD90 prolongation after amiodarone treatment","predicted":"APD90 prolongation","reason":"Human ventricular APD90 prolongation agrees with the modeled direction at all active doses.","limitations":"Loading/chronic treatment includes metabolites and remodeling absent from the acute 10-beat model. Oral mg/day is not converted to bath µM; conduction and amplitude were not comprehensively compared.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/8353868/","title":"Frequency-dependent electrophysiologic effects of amiodarone in humans (Sager et al., 1993)","endpoint":"Ventricular APD90","system":"19 loading and 15 chronic-treatment patients","exposure":"11 days loading at 1621 ± 162 mg/day; chronic 380 ± 56 mg/day; paced cycles 300–600 ms","claim":"APD90 increased about 30 ms, 10–13%, p < .001 at all paced cycles.","locator":"Abstract methods/results; DOI 10.1161/01.cir.88.3.1063"}]},{"number":38,"display_number":38,"drug":"Amitriptyline","studies":[48],"grade":"partial","observed":"Amitriptyline APD shortening followed by prolongation; little change at low exposure","predicted":"APD90 shortening","reason":"Small modeled shortening captures the initial dog response but not subsequent prolongation. A low-exposure canine wedge study found unchanged APD90; the small model response is compatible with that limited observation.","limitations":"Model 0.0364–0.1456 µM is below the 0.2 µM wedge exposure and below toxic infusions. Infusion mg/kg/min cannot be treated as bath µM. The model does not represent tissue reentry.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/7509896/","title":"Mechanisms of ventricular arrhythmia during amitriptyline toxicity","endpoint":"Monophasic APD50/APD90","system":"23 anesthetized dogs","exposure":"Graded infusion 0.5–1 mg/kg/min","claim":"APD shortened then prolonged as serum concentrations rose; afterdepolarizations were not detected.","locator":"Abstract results"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3468832/","title":"Ionic and Cellular Mechanisms Underlying the Development of Acquired Brugada Syndrome in Patients Treated with Antidepressants","endpoint":"APD90","system":"Canine right-ventricular wedge","exposure":"0.2 µM amitriptyline alone","claim":"APD90 and QRS were unchanged; separate provocation conditions are not the monotherapy comparison.","locator":"Results: Amitriptyline Induction of Phase 2 Reentry; Table 1A"}]},{"number":39,"display_number":39,"drug":"Azithromycin","studies":[49],"grade":"full","observed":"Azithromycin exposure associated with measured QT prolongation","predicted":"APD90 prolongation","reason":"Modeled APD90 prolongation agrees with the positive QT association in the clinical ECG study. This supports effect direction rather than a clinical risk probability.","limitations":"Clinical QTc is distinct from single-cell APD90. Observational associations can include disease and co-medication; not every clinical cohort shows prolongation. Independent guinea-pig ECG/APD evidence also supports prolongation, but at substantially higher exposures; it does not validate the modeled low-dose response.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/30406128/","title":"Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice (Choi et al., 2018)","endpoint":"QTc prolongation","system":"402,607 subjects, hospital ECG/EHR case-control analysis","exposure":"Azithromycin prescription exposure; individual plasma concentrations unavailable","claim":"QT prolongation OR 1.40, 95% CI 1.23–1.59; severe QT prolongation OR 1.43, 1.13–1.82.","locator":"Abstract results; DOI 10.1155/2018/1574806"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28213753/","title":"Electrophysiologic Studies on the Risks and Potential Mechanism Underlying the Proarrhythmic Nature of Azithromycin","endpoint":"QTc; APD50 and APD90","system":"Guinea-pig in-vivo ECG, isolated heart ECG and ventricular cardiomyocytes","exposure":"114.6 mg/kg in vivo; 207.5/415 mg/L in isolated hearts; APD prolongation at 830 mg/L","claim":"Azithromycin prolonged measured QTc at high exposure; ventricular APD50/APD90 significantly lengthened at 830 mg/L.","locator":"Primary abstract Results"}]},{"number":41,"display_number":40,"drug":"Chloroquine","studies":[51],"grade":"full","observed":"Chloroquine concentration-dependent APD prolongation","predicted":"APD90 prolongation","reason":"Modeled prolongation agrees with measured feline Purkinje and ventricular APD prolongation over an overlapping exposure range.","limitations":"Model 0.2495–0.998 µM overlaps only the lower part of the 0.3–10 µM experimental range. Higher-dose automaticity and resting-potential effects were not quantitatively validated.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/11259572/","title":"Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes (Sánchez-Chapula et al.)","endpoint":"APD","system":"Cat Purkinje fibers and ventricular myocytes","exposure":"0.3–10 µM","claim":"APD increased with concentration; upstroke velocity fell, with automaticity and depolarization at higher doses.","locator":"Abstract Results"}]},{"number":42,"display_number":41,"drug":"Cibenzoline","studies":[52],"grade":"partial","observed":"Cibenzoline APD prolongation in dog; unchanged/shortened APD in guinea-pig preparations","predicted":"APD90 prolongation","reason":"Modeled prolongation captures the canine ventricular branch. Published guinea-pig experiments report unchanged or shortened APD, so preparation-dependent findings are only partly reproduced.","limitations":"Model 0.673–2.692 µM is mostly below the canine significant-effect exposure of 3 µM. Opposing guinea-pig findings remain explicit; the result is not a match across every preparation.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://www.jstage.jst.go.jp/article/jphs1951/44/2/44_2_113/_pdf","title":"Effect of Cibenzoline, a Class I Antiarrhythmic Drug, on Action Potential in Canine Ventricular Muscle (Satoh et al., 1987)","endpoint":"APD90","system":"Canine right-ventricular papillary muscle, 60 beats/min","exposure":"0.8, 3 and 8 µM; 15–20 minutes equilibration","claim":"APD90 increased 26% at 3 µM and 30% at 8 µM, n = 6; no significant effect at 0.8 µM.","locator":"Results page 114; Figure 1 and Table 1; DOI 10.1254/jjp.44.113"},{"url":"https://pubmed.ncbi.nlm.nih.gov/7527502/","title":"Effects of cibenzoline, a new class Ia antiarrhythmic drug, on various membrane ionic currents and action potentials of guinea-pig ventricular cells (Sato et al., 1994)","endpoint":"APD30/APD90","system":"Single guinea-pig ventricular cells, 0.2 Hz, 32–33°C","exposure":"5, 10 and 30 µM","claim":"APD30 and APD90 shortened significantly at all tested exposures.","locator":"Abstract item 3; DOI 10.1007/BF00241092"},{"url":"https://pubmed.ncbi.nlm.nih.gov/3806408/","title":"Characterization of the class I antiarrhythmic activity of cibenzoline succinate in guinea pig papillary muscle (Arena et al., 1987)","endpoint":"APD50/APD90","system":"Guinea-pig papillary muscle","exposure":"1–128 µM","claim":"APD50 and APD90 were unchanged.","locator":"Abstract"}]},{"number":43,"display_number":42,"drug":"Cilostazol","studies":[53],"grade":"full","observed":"Cilostazol-associated clinical QTc prolongation","predicted":"APD90 prolongation","reason":"Clinical QTc prolongation aligns with modeled APD90 prolongation. Raw QT did not change significantly in this cohort; the two endpoints are kept distinct.","limitations":"Clinical disease, rate correction and chronic PDE/cAMP mechanisms differ from acute ORd channel scaling. Oral mg is not converted to µM. This is qualitative support, not clinical validation.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://kosuyoluheartjournal.com/full-text/1882/eng","title":"The Effect of Cilostazol on Electrocardiographic Parameters in Patients with Peripheral Artery Disease Initiating Cilostazol Treatment (Omar et al., 2023)","endpoint":"QTc","system":"32 patients with peripheral artery disease, before/after ECG","exposure":"100 mg twice daily for 3 months","claim":"QTc increased from 414.34 ± 32.46 to 430.93 ± 33.25 ms, p = .01; raw QT was not significantly changed.","locator":"Abstract; Results; Table 2; DOI 10.51645/khj.2023.m347"}]},{"number":44,"display_number":43,"drug":"Dasatinib","studies":[54],"grade":"partial","observed":"Dasatinib-associated QTc prolongation; model response is minimal","predicted":"Minimal APD90 change","reason":"The positive model sign agrees with clinical QTc prolongation, but every modeled APD change is below 1 ms and is displayed as Minimal APD90 change. Only a weak signal is captured.","limitations":"Model changes of +0.07 to +0.37 ms are minimal under the existing descriptive rule. A sign match does not establish a clinically meaningful warning. The reported clinical 30 ± 9.7 ms change applies only to affected cases, not all 115 administrations.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8772338/","title":"Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors (Abu Rmilah et al., 2020)","endpoint":"QTcF","system":"115 dasatinib administrations in cancer patients","exposure":"20–140 mg/day among affected cases; most at least 70 mg/day","claim":"48/115 administrations showed QTc prolongation; selected affected cases had mean pre/post change 30 ± 9.7 ms.","locator":"Table 2; Figure 1 affected cases; Table 3; DOI 10.1002/ijc.33119"}]},{"number":45,"display_number":44,"drug":"Desipramine","studies":[55],"grade":"full","observed":"Desipramine acute and chronic ventricular APD prolongation","predicted":"APD90 prolongation","reason":"The positive model APD trend agrees with primary acute ventricular observations. Chronic trafficking and apoptosis findings are limitations, not claimed model predictions.","limitations":"Model 0.108–0.432 µM is below acute 1 and 10 µM experiments. APD100 differs from APD90; static block does not represent trafficking or apoptosis.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/21120454/","title":"hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine (Staudacher et al., 2011)","endpoint":"APD100","system":"Fresh guinea-pig ventricular myocytes; chronic cultures separately","exposure":"Acute 1 and 10 µM; overnight 30 µM","claim":"Acute and chronic desipramine prolonged APD.","locator":"Abstract; Figure 8 in author PDF at https://publikationen.bibliothek.kit.edu/110082077/150185141; DOI 10.1007/s00210-010-0583-9"}]},{"number":46,"display_number":45,"drug":"Diazepam","studies":[56],"grade":"full","observed":"Diazepam alone did not prolong APD","predicted":"Minimal APD90 change","reason":"Every modeled absolute APD90 change is below 1 ms, agreeing with no APD prolongation from diazepam alone. Tiny modeled shortening is not presented as a measured clinical effect.","limitations":"Model 0.029–0.116 µM is below the tested 1 µM. The less-than-1-ms rule is descriptive, not a statistical or safety threshold. The methadone interaction is a separate combination experiment.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/20930594/","title":"Increased cardiac risk in concomitant methadone and diazepam treatment: pharmacodynamic interactions in cardiac ion channels","endpoint":"APD","system":"Human stem cell-derived cardiomyocytes","exposure":"Diazepam 1 µM alone; methadone combination studied separately","claim":"Diazepam alone had no APD effect at 1 µM; combination-induced prolongation is a separate result.","locator":"Abstract Results"}]},{"number":47,"display_number":46,"drug":"Diphenhydramine","studies":[57],"grade":"full","observed":"Diphenhydramine mild clinical QTc prolongation and experimental MAPD lengthening","predicted":"APD90 prolongation","reason":"Small positive model APD changes agree with measured clinical and whole-heart repolarization lengthening.","limitations":"Model 0.034–0.136 µM is below reported total plasma concentration around 0.7 µM and bath exposure of 10 µM. Free and total exposure are not interchangeable; clinical QT and MAPD are distinct from model APD90.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/9918600/","title":"Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine (Khalifa et al., 1999)","endpoint":"QTc/MAPD","system":"Humans and isolated guinea-pig hearts","exposure":"Usual oral dose total plasma about 0.7 µM; heart bath 10 µM","claim":"QTc increased above 20 ms in 7/20 patients; 10 µM lengthened MAPD; most usual-dose effects were modest.","locator":"Abstract clinical and isolated-heart results"}]},{"number":48,"display_number":47,"drug":"Donepezil","studies":[58],"grade":"full","observed":"Donepezil-associated QT prolongation in clinical ECG cohorts","predicted":"APD90 prolongation","reason":"Modeled APD prolongation agrees with longer-term clinical QT/QTc increases. A separate 4-week study found no significant QT change; that negative result is retained as a qualification.","limitations":"Not all cohorts show significant prolongation. Clinical QTc with disease and co-medication differs from single-cell APD90. Absence of model EAD flags does not establish absence of clinical TdP risk.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/32609550/","title":"Long term use of donepezil and QTc prolongation","endpoint":"QT/QTc","system":"59 patients with before/after ECG","exposure":"Long-term treatment; exact plasma µM unavailable","claim":"QT increased from 393.3 ± 35.6 to 411.9 ± 44.6 ms, p = .002; rate-corrected change also significant.","locator":"Abstract Results"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7956884/","title":"Effect of QT Prolongation in Patients Taking Cholinesterase Inhibitors (Donepezil) for Alzheimer’s Disease","endpoint":"QTc","system":"57 treated patients and 57 controls; 46 before/after observations","exposure":"Clinical donepezil treatment","claim":"Within 46 patients, QTc rose from 433 ± 34 to 442 ± 33 ms, p = .014.","locator":"Table 4"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5937610/","title":"Electrocardiogram Changes of Donepezil Administration in Elderly Patients with Ischemic Heart Disease","endpoint":"QT/QTc","system":"60 patients with ischemic heart disease","exposure":"5 mg/day for at least 4 weeks","claim":"No significant QT-parameter change; QTc 415.1 ± 35.7 to 424.3 ± 37.2 ms, p = .7529.","locator":"Abstract; Table 3"}]},{"number":49,"display_number":48,"drug":"Duloxetine","studies":[59],"grade":"full","observed":"Duloxetine thorough-QT study showed no QT prolongation","predicted":"Minimal APD90 change","reason":"Every modeled paired APD90 change is below 1 ms, compatible with absence of QT prolongation in the controlled clinical study. The observed small QTc decrease is not claimed to be reproduced.","limitations":"Model +0.04 to +0.28 ms is displayed as Minimal APD90 change under the existing descriptive rule, not a statistical or safety threshold. This compares absence of prolongation; oral dose is not converted to µM.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/17414226/","title":"QT effects of duloxetine at supratherapeutic doses: a placebo and positive controlled study (Zhang et al., 2007)","endpoint":"QTc","system":"117 healthy women; randomized placebo and moxifloxacin controlled crossover","exposure":"60 mg twice daily escalated to 200 mg twice daily; exposure above 5 times therapeutic","claim":"No QT prolongation; mean QTc decreased versus placebo at 200 mg twice daily; no concentration relationship.","locator":"Abstract Results/Conclusion; DOI 10.1097/FJC.0b013e318030aff7"}]},{"number":50,"display_number":49,"drug":"Flecainide","studies":[60],"grade":"full","observed":"Measured rabbit QT and hiPSC CTD90 prolongation","predicted":"APD90 prolongation","reason":"CARDIX prolongation is directionally consistent with measured rabbit QT and human stem-cell calcium-transient prolongation at 1 and 10 µM; these experimental endpoints differ from model APD90.","limitations":"The 1uM source dose is approximately1.33x source free Cmax and falls within the model's0.752–3.008uM dose range;10uM is higher exposure.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"QT interval","system":"left ventricular rabbit wedge ECG","exposure":"Rabbit wedge ECG QT as described in Lu2016 and Passini2017; changes compared with baseline, vehicle QT cutoff5%.","claim":"prolongation","locator":"Figure 5, Flecainide rows, experimental QT interval column only"},{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"CTD90","system":"spontaneously beating Cor.4U hiPSC-CMs, calcium fluorescence","exposure":"Cor.4U monolayers at37C; spontaneous calcium fluorescence using FDSS6000/Calcium5; CTD90 at25min after compound addition; source relevance cutoff25%.","claim":"prolongation","locator":"Figure 5, Flecainide rows, experimental CTD90 column only"}]},{"number":51,"display_number":50,"drug":"Fluvoxamine","studies":[61],"grade":"full","observed":"Fluvoxamine caused slight measured QTc prolongation","predicted":"APD90 prolongation","reason":"The positive model APD trend agrees with slight QTc prolongation in the guinea-pig experiment, without validating clinical magnitude or probability.","limitations":"Systemic infusion is not converted to bath µM. QTc differs from APD90. Fluvoxamine produced a weaker signal than imipramine in the primary study; model +14 to +51 ms is not a validated effect size.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://www.jstage.jst.go.jp/article/bpb/24/5/24_5_550/_article","title":"A Comparative Pharmacodynamic Study of the Arrhythmogenicity of Antidepressants, Fluvoxamine and Imipramine, in Guinea Pigs (Ohtani et al., 2001)","endpoint":"QTc","system":"Anesthetized guinea-pigs with ECG and plasma concentration recording","exposure":"Fluvoxamine 20 mg/kg/hour intravenously for 90 minutes","claim":"Fluvoxamine prolonged QTc slightly; imipramine caused distinct dose-dependent prolongation.","locator":"Abstract Results; DOI 10.1248/bpb.24.550"}]},{"number":52,"display_number":51,"drug":"Halofantrine","studies":[62],"grade":"full","observed":"Halofantrine concentration-related clinical QTc prolongation","predicted":"APD90 prolongation","reason":"Monotonic model APD90 prolongation agrees with the positive concentration–QTc relationship observed in humans.","limitations":"Stereoselective free/total exposure, systemic dosing and malaria physiology differ from ORd channel block. Oral or intravenous mg is not converted to µM; no clinical risk probability is inferred.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/11298069/","title":"Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation","endpoint":"QTc","system":"Healthy adults; 21 enrolled, 13 completed, 16 active and 5 placebo initially","exposure":"Racemic halofantrine 500 mg/day for 42 days; serial enantiomer concentrations","claim":"14/16 active subjects had QTc prolongation positively correlated with both enantiomer concentrations.","locator":"Abstract Results/Conclusion"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12959277/","title":"Pharmacokinetics, efficacy and toxicity of parenteral halofantrine in uncomplicated malaria (Krishna et al., 1993)","endpoint":"QT/QTc","system":"12 adults with acute malaria and 9 convalescent adults","exposure":"1 mg/kg intravenously over 1 hour, every 8 hours, 3 doses","claim":"After third dose, QTc prolonged 8.2 ± 5.6% (SD), p < .001.","locator":"Abstract item 4; DOI 10.1111/j.1365-2125.1993.tb00419.x"}]},{"number":53,"display_number":52,"drug":"Haloperidol","studies":[63],"grade":"partial","observed":"Haloperidol measured APD prolongation; response can be biphasic","predicted":"APD90 prolongation","reason":"The model captures the reported prolonging branch, but the primary experiments describe biphasic and preparation-dependent APD behavior. The selected model doses are also far below the cited 3 µM example. Only part of the reported response is captured, consistently with other partial compound reviews.","limitations":"Model 0.004–0.016 µM is far below the 3 µM experimental example. Species and ischemia protocols differ. Only the prolonging branch is captured; high-dose biphasic behavior is not demonstrated.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/17640477/","title":"Electrophysiological effects of haloperidol on isolated rabbit Purkinje fibers and guinea pigs papillary muscles under normal and simulated ischemia (Yan et al., 2007)","endpoint":"APD90","system":"Rabbit Purkinje fibers and guinea-pig papillary muscle","exposure":"Micromolar series; significant Purkinje prolongation at 3 µM","claim":"Under ischemia Purkinje APD90 prolonged concentration-dependently; papillary responses depended on condition.","locator":"Abstract Results; DOI 10.1111/j.1745-7254.2007.00572.x"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17596973/","title":"Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization (Terrar et al., 2007)","endpoint":"APD90","system":"Guinea-pig ventricular myocytes and dog Purkinje fibers","exposure":"Full concentration grid not recovered","claim":"Haloperidol showed biphasic APD responses; the prolonging branch exceeded 25% in guinea-pig myocytes.","locator":"Primary PubMed abstract; DOI 10.1016/j.vascn.2007.04.005"}]},{"number":54,"display_number":53,"drug":"Imipramine","studies":[64],"grade":"partial","observed":"Imipramine systemic QTc prolongation but ventricular/Purkinje APD shortening in other preparations","predicted":"APD90 prolongation","reason":"Model prolongation captures systemic QTc prolongation in Ohtani 2001. It does not reproduce shortening in bovine ventricular and canine Purkinje experiments; endpoint and preparation heterogeneity require a qualified partial result.","limitations":"Model 0.106–0.424 µM is below the bovine shortening threshold above 1 µM. QTc includes conduction and rate correction and is not identical to cellular APD. No exposure-route conversion is attempted.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://www.jstage.jst.go.jp/article/bpb/24/5/24_5_550/_article","title":"A Comparative Pharmacodynamic Study of the Arrhythmogenicity of Antidepressants, Fluvoxamine and Imipramine, in Guinea Pigs (Ohtani et al., 2001)","endpoint":"QTc","system":"Anesthetized guinea-pigs","exposure":"Imipramine 10 and 20 mg/kg/hour intravenously for 90 minutes","claim":"Distinct dose-dependent QTc prolongation.","locator":"Abstract Results; DOI 10.1248/bpb.24.550"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2044363/","title":"Electrophysiological effects of imipramine on bovine ventricular muscle and Purkinje fibres","endpoint":"APD","system":"Bovine ventricular muscle and Purkinje fibers","exposure":"Ventricular shortening above 1 µM","claim":"Ventricular APD shortened; Purkinje APD was unchanged; phase-2 amplitude decreased.","locator":"Abstract items 3/4"},{"url":"https://pubmed.ncbi.nlm.nih.gov/7416020/","title":"Electrophysiologic effects of imipramine and doxepin on normal and depressed cardiac Purkinje fibers","endpoint":"APD/APA/Vmax","system":"Canine Purkinje fibers","exposure":"Dose-related exposure; exact concentration grid unavailable","claim":"Dose-related decreases in APD, amplitude, upstroke velocity and conduction velocity.","locator":"Abstract Results"}]},{"number":56,"display_number":54,"drug":"Lidocaine","studies":[66],"grade":"partial","observed":"Rabbit QT shortening; hiPSC CTD90 prolongation","predicted":"APD90 shortening","reason":"CARDIX shortening agrees with measured rabbit QT shortening at 10 and 100 µM, while stem-cell CTD90 prolongs; the supporting literature therefore shows mixed endpoint agreement.","limitations":"The10uM source dose is approximately3.85x Passini2017 free Cmax and lies near the model's highest dose10.2416uM;100uM is higher exposure. The selected model exposure is2.5604uM from Zhou2020 and remains distinct from Passini2017's2.6uM.","label":"Relevant Effect Captured","detail":"Partial agreement","review_origin":"supporting_literature","sources":[{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"QT interval","system":"left ventricular rabbit wedge ECG","exposure":"Rabbit wedge ECG QT as described in Lu2016 and Passini2017; changes compared with baseline, vehicle QT cutoff5%.","claim":"shortening","locator":"Figure 5, Lidocaine rows, experimental QT interval column only"},{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"CTD90","system":"spontaneously beating Cor.4U hiPSC-CMs, calcium fluorescence","exposure":"Cor.4U monolayers at37C; spontaneous calcium fluorescence using FDSS6000/Calcium5; CTD90 at25min after compound addition; source relevance cutoff25%.","claim":"prolongation","locator":"Figure 5, Lidocaine rows, experimental CTD90 column only"}]},{"number":57,"display_number":55,"drug":"Linezolid","studies":[67],"grade":"full","observed":"Transient early QTcF shortening after linezolid; no clinically significant QTc prolongation in a controlled thorough-QT study.","predicted":"APD90 shortening","reason":"The modeled shortening direction agrees with the directly measured early shortening after both clinical dose levels. Agreement is directional; the source effect was transient and much smaller than the modeled response, and the source does not establish sustained QT shortening.","limitations":"Clinical QTcF and cellular APD90 are distinct endpoints. The experiment's oral/IV administered doses are not converted into fabricated µM coordinates. The short-lived observed effect is not evidence for a persistent clinical shortening of 15–21 ms.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3165302/","title":"Lack of an Effect of Standard and Supratherapeutic Doses of Linezolid on QTc Interval Prolongation","endpoint":"Time-matched placebo-corrected QTcF","system":"Randomized placebo- and moxifloxacin-controlled four-way crossover in 40 healthy subjects","exposure":"Single 600 or 1,200 mg IV infusions over 60 minutes","claim":"At 1 and 2 hours, QTcF changes were −2.96/−5.53 ms after 600 mg and −1.78/−7.51 ms after 1,200 mg. Shortening was absent by 4 hours; the study was negative for clinically significant QTc prolongation.","locator":"Results, Electrocardiography; Figure 1"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21709083/","title":"Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation","endpoint":"QTcF","system":"Healthy volunteers","exposure":"600/1,200 mg IV; oral moxifloxacin control","claim":"Independent bibliographic verification of the same primary randomized trial, DOI 10.1128/AAC.01723-10.","locator":"Abstract and publication metadata"}]},{"number":58,"display_number":56,"drug":"Lopinavir","studies":[68],"grade":"partial","observed":"Isolated lopinavir prolonged rabbit QT, with unchanged average APD90; chronic hiPSC exposure shortened APD90 and acute exposure produced EADs.","predicted":"APD90 prolongation","reason":"The model captures the direction of measured rabbit QT prolongation. It does not reproduce the same experiment's unchanged average APD90, the chronic hiPSC APD90 shortening, or observed acute EADs. These endpoint- and duration-dependent differences support partial agreement rather than full agreement.","limitations":"The highest model dose is near, but below, the lowest rabbit dose of 3 µM; 5–10 µM is higher exposure. Chronic remodeling over 24 hours differs from the model's 10 paced cycles. QT, average APD90 and EAD presence must remain separate observations; no numerical EAD incidence is fabricated.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[{"dose":3,"mean":4,"sem":null,"n":12,"unit":"ms","endpoint":"QT change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":253,"treated_mean":257,"error_note":"Published marginal SDs are 27 and 29 ms; paired-change SEM was not supplied and is not invented.","assay":"Langendorff-perfused rabbit heart"},{"dose":5,"mean":15,"sem":null,"n":12,"unit":"ms","endpoint":"QT change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":253,"treated_mean":268,"error_note":"Published marginal SDs are 27 and 30 ms; paired-change SEM was not supplied.","assay":"Langendorff-perfused rabbit heart"},{"dose":10,"mean":25,"sem":null,"n":12,"unit":"ms","endpoint":"QT change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":253,"treated_mean":278,"error_note":"Published marginal SDs are 27 and 32 ms; paired-change SEM was not supplied.","assay":"Langendorff-perfused rabbit heart"},{"dose":3,"mean":-5,"sem":null,"n":12,"unit":"ms","endpoint":"APD90 change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":168,"treated_mean":163,"significance":"not significant","assay":"Langendorff-perfused rabbit heart"},{"dose":5,"mean":0,"sem":null,"n":12,"unit":"ms","endpoint":"APD90 change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":168,"treated_mean":168,"significance":"not significant","assay":"Langendorff-perfused rabbit heart"},{"dose":10,"mean":-4,"sem":null,"n":12,"unit":"ms","endpoint":"APD90 change (difference of group means)","system":"Langendorff-perfused rabbit heart","source":"Wolfes et al. 2024","url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","baseline_mean":168,"treated_mean":164,"significance":"not significant","assay":"Langendorff-perfused rabbit heart"},{"dose":10,"mean":-191.8,"sem":null,"n":14,"unit":"ms","endpoint":"APD90 change after 24-hour exposure (difference of group means)","system":"hiPSC-derived cardiomyocytes","source":"Zheng et al. 2022","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9301601/","baseline_mean":364.4,"treated_mean":172.6,"significance":"p < 0.0001","assay":"hiPSC-derived cardiomyocytes"}],"sources":[{"url":"https://link.springer.com/article/10.1007/s12012-024-09872-3","title":"Electrophysiological Profile of Different Antiviral Therapies in a Rabbit Whole-Heart Model","endpoint":"QT, monophasic APD90 and repolarization dispersion","system":"Langendorff-perfused AV-blocked rabbit hearts; lopinavir group n=12","exposure":"3, 5 and 10 µM isolated lopinavir, without ritonavir; paced cycle lengths 300–900 ms","claim":"QT increased from 253 ms to 257, 268 and 278 ms, whereas average APD90 was not significantly changed (168 ms baseline; 163, 168, 164 ms).","locator":"Results, Lopinavir; Figure 4"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9301601/","title":"Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether-à-go-go–Related Gene and Cav1.2","endpoint":"APD90 and EAD presence","system":"hiPSC-derived ventricular-like cardiomyocytes","exposure":"10 µM lopinavir; 24-hour incubation for duration, within 1 hour for EAD examples","claim":"APD90 fell from 364.4 to 172.6 ms after 24 hours (n=14). EADs were recorded during acute treatment.","locator":"Results, Figure 6C–H and associated text"}]},{"number":59,"display_number":57,"drug":"Methadone","studies":[69],"grade":"full","observed":"Clinical QTc prolongation during methadone maintenance treatment.","predicted":"APD90 prolongation","reason":"Modeled concentration-dependent prolongation agrees with measured QTc prolongation in a randomized methadone trial. This verdict concerns repolarization direction, not prediction of individual clinical QTc magnitude or TdP.","limitations":"Clinical QTc is not cellular APD90. Long-term clinical treatment, pharmacokinetics and patient comorbidity differ from 10-cycle cellular simulation. No clinical EAD or TdP claim is inferred from the absence of a cellular EAD flag.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/18071169/","title":"QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial","endpoint":"QTc and increase from baseline","system":"17-week randomized double-blind trial; ECGs from 165 opioid-dependent participants","exposure":"Methadone maintenance treatment with ECGs at baseline and every 4 weeks","claim":"Methadone-treated participants developed prolonged QTc and increases from baseline more frequently than buprenorphine-treated participants.","locator":"Abstract, Results; JAMA full text Figure 2"},{"url":"https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/770013","title":"QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial","endpoint":"Longitudinal QTc","system":"Human randomized trial","exposure":"Maintenance treatment over 17 weeks","claim":"The original primary trial demonstrates an increasing QTc trajectory under methadone.","locator":"Results and Figure 2"}]},{"number":60,"display_number":58,"drug":"Metronidazole","studies":[70],"grade":"full","observed":"QTc prolongation after IV metronidazole in a susceptible patient, reversing after withdrawal.","predicted":"Mixed APD90 response","reason":"The model produces the reported prolongation direction at higher tested concentrations. Under the stated any-modeled-dose criterion this captures the observed effect; it does not establish the source patient's exposure, the mechanism, or the clinical magnitude.","limitations":"Single susceptible patient; concomitant medications and an unproven mechanism limit causal generalization. No µM concentration is recoverable for the clinical observation, so no false dose-response point is plotted. The modeled initial shortening has no corresponding observation in this case report.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/21733783/","title":"QT interval prolongation due to metronidazole administration","endpoint":"Clinical QTc","system":"71-year-old woman with multiple cardiovascular/pulmonary conditions and prior drug-induced QT prolongation","exposure":"IV metronidazole; change occurred after 2 days; exact administered dose and plasma concentration not stated in the recovered report","claim":"Primary case report of QTc prolongation during metronidazole treatment.","locator":"Primary letter metadata, DOI 10.5152/akd.2011.120"},{"url":"https://anatoljcardiol.com/storage/upload/pdfs/AnatolJCardiol_11_5_468_469.pdf","title":"QT interval prolongation due to metronidazole administration","endpoint":"QTc before and after treatment","system":"Clinical case report","exposure":"IV metronidazole for nosocomial pneumonia","claim":"QTc increased from 396 to 559 ms after 2 days, with normal potassium/magnesium; ECG normalized within 48 hours after discontinuation.","locator":"Page 468, case paragraph and Figures 1–2; page 469, susceptibility and mechanism discussion"}]},{"number":61,"display_number":59,"drug":"Mibefradil","studies":[71],"grade":"not_predicted","observed":"Human and guinea-pig cardiomyocyte AP plateau shortening; dog MAP/QT did not prolong. Rabbit cardiodepressant exposure caused only nonsignificant slight MAP lengthening.","predicted":"APD90 prolongation","reason":"The selected model regimen does not reproduce the primary study's consistent cellular shortening or in-vivo absence of QT prolongation. A nonsignificant slight lengthening in a different rabbit high-exposure preparation is retained as mixed context, not treated as confirmed prolongation matching the modeled trend.","limitations":"The source comprises multiple species, endpoints and exposure levels. The complete cellular concentration grid was not recovered; this is a direction comparison, not a dose-matched challenge. No statistical confidence is assigned to the source's nonsignificant rabbit lengthening.","label":"Effect Not Captured","detail":"At tested model exposures","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/10640293/","title":"Effects of the T-type Ca(2+) channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue","endpoint":"Cardiac AP/MAP duration and QT","system":"Isolated guinea-pig and human cardiomyocytes, rabbit hearts, open-chest bradycardic dogs and other preparations","exposure":"Dose-dependent cellular effects and noncardiodepressant/cardiodepressant whole-heart exposure; exact concentration range not recovered from abstract","claim":"Mibefradil shortened human/guinea-pig AP plateau; dog MAPs shortened slightly with no QT effect. Rabbit high cardiodepressant concentrations produced slight nonsignificant lengthening.","locator":"Primary abstract, Results and Conclusion"}]},{"number":62,"display_number":60,"drug":"Mitoxantrone","studies":[72],"grade":"not_predicted","observed":"APD prolongation and occasional EADs in guinea-pig ventricular myocytes exposed to 30 µM mitoxantrone.","predicted":"APD90 shortening","reason":"Neither the reported prolongation direction nor EAD presence was observed anywhere in the selected modeled range. The primary experimental dose of 30 µM is approximately 33 times the highest modeled dose, so the result is a failure to capture this literature effect in the chosen regimen, not evidence that CARDIX would fail at 30 µM.","limitations":"The relevant experimental effect was measured at much higher concentration than the completed model grid. Species and time dependence differ from the 10-cycle human ORd simulation. No numerical APD or EAD incidence is invented from the qualitative abstract.","label":"Effect Not Captured","detail":"At tested model exposures","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC1566021/","title":"Effects of mitoxantrone on action potential and membrane currents in isolated cardiac myocytes","endpoint":"Ventricular APD and EAD presence","system":"Whole-cell-clamped isolated guinea-pig ventricular myocytes","exposure":"30 µM mitoxantrone; time-dependent effect and reverse rate dependence","claim":"Mitoxantrone prolonged APD and sometimes induced EADs; IKr and IK1 depression was measured.","locator":"Abstract items 2–3 and conclusion; PMID 10385229"}]},{"number":63,"display_number":61,"drug":"Moxifloxacin","studies":[73],"grade":"full","observed":"Measured rabbit QT and hiPSC CTD90 prolongation","predicted":"APD90 prolongation","reason":"CARDIX prolongation is directionally consistent with measured rabbit QT increases at 10–30 µM and stem-cell CTD90 prolongation at 30 µM.","limitations":"The10/30uM source doses are approximately0.91/2.74x source free Cmax, bracketing or within the model's10.96–43.84uM range;300uM is higher exposure. QT at300uM and CTD90 at10uM were not tested.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"QT interval","system":"left ventricular rabbit wedge ECG","exposure":"Rabbit wedge ECG QT as described in Lu2016 and Passini2017; changes compared with baseline, vehicle QT cutoff5%.","claim":"prolongation","locator":"Figure 5, Moxifloxacin rows, experimental QT interval column only"},{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"CTD90","system":"spontaneously beating Cor.4U hiPSC-CMs, calcium fluorescence","exposure":"Cor.4U monolayers at37C; spontaneous calcium fluorescence using FDSS6000/Calcium5; CTD90 at25min after compound addition; source relevance cutoff25%.","claim":"prolongation","locator":"Figure 5, Moxifloxacin rows, experimental CTD90 column only"}]},{"number":64,"display_number":62,"drug":"Nilotinib","studies":[74],"grade":"full","observed":"Increasing nilotinib exposure was associated with increasing clinical QTcF.","predicted":"APD90 prolongation","reason":"The model's increasing prolongation across concentration agrees with the measured clinical exposure-QTcF direction. This does not imply numerical QTcF calibration, individual clinical arrhythmia prediction, or equal free/total concentrations.","limitations":"Clinical QTcF is not cellular APD90; the clinical data do not validate the modeled magnitude. Serum total concentration is distinct from the model's free concentration grid. The overall clinical cohort median was stable despite individual prolongation; the positive exposure-response study supplies the graded direction.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5557053/","title":"Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase","endpoint":"Time-matched serum nilotinib concentration and QTcF change","system":"Clinical ENESTnd exposure-response analysis; 542 patients contributed pharmacokinetic data","exposure":"Nilotinib 300 or 400 mg twice daily; concentration/QTcF pairs on days 8 and 84","claim":"A positive correlation was observed between measured nilotinib concentration and QTcF change from baseline.","locator":"Results, Exposure-safety relationship; Figure 5"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3366654/","title":"Clinical cardiac safety profile of nilotinib","endpoint":"QTcF longitudinal follow-up","system":"81 nilotinib-treated CML patients","exposure":"Median treatment 26 months","claim":"QTcF increases greater than 30 ms occurred in 18 patients and greater than 60 ms in two; cohort median QTcF did not change significantly.","locator":"Results, Cardiac function and Figure 1A"}]},{"number":65,"display_number":63,"drug":"Nimodipine","studies":[75],"grade":"full","observed":"Rabbit QT shortening at higher exposure","predicted":"APD90 shortening","reason":"CARDIX shortening shares the measured rabbit QT direction at 0.1–1 µM; these experiments used much higher concentrations than this study's 1–4× exposure range.","limitations":"Only higher-exposure direction support:0.1/1uM are100/1000x source free Cmax, above the model's0.001–0.004uM range. CTD90 changes(+7/−14%) do not exceed the source's25% assay relevance cutoff.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"QT interval","system":"left ventricular rabbit wedge ECG","exposure":"Rabbit wedge ECG QT as described in Lu2016 and Passini2017; changes compared with baseline, vehicle QT cutoff5%.","claim":"shortening","locator":"Figure 5, Nimodipine rows, experimental QT interval column only"},{"url":"https://doi.org/10.3389/fphys.2017.00668","title":"Passini et al. 2017","endpoint":"CTD90","system":"spontaneously beating Cor.4U hiPSC-CMs, calcium fluorescence","exposure":"Cor.4U monolayers at37C; spontaneous calcium fluorescence using FDSS6000/Calcium5; CTD90 at25min after compound addition; source relevance cutoff25%.","claim":"small mixed changes below source relevance cutoff","locator":"Figure 5, Nimodipine rows, experimental CTD90 column only"}]},{"number":66,"display_number":64,"drug":"Nisoldipine","studies":[76],"grade":"full","observed":"APD90 shortening in guinea-pig ventricular myocytes, canine ventricular tissue and susceptible human iPSC-derived cardiomyocytes.","predicted":"APD90 shortening","reason":"The model captures the repeatedly measured shortening direction. The recovered experiments used much higher concentrations and some diseased-cell preparations, so this is qualitative direction support rather than validation of the response at the model's very low exposure.","limitations":"The lowest recovered experimental concentration, 0.05 µM, is 125 times the highest model concentration; 0.2–1 µM is still higher. The human cell experiment used a familial LQT2 phenotype; it is not a healthy-cell quantitative benchmark. Published difference-of-means is labeled as such, not paired-change SEM.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[{"dose":1,"mean":-28,"sem":null,"n":7,"unit":"ms","endpoint":"APD90 change (difference of group means)","system":"Canine ventricular myocardium, 500-ms cycle length","source":"The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium (2021)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8371021/","baseline_mean":187,"treated_mean":159,"error_note":"Marginal reported errors of 5 ms are retained in the source; the paired-change error was not recovered and is not synthesized.","significance":"p < 0.05","assay":"Canine ventricular myocardium, 500-ms cycle length"}],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/9335409/","title":"Multiple modulations of action potential duration by different calcium channel blocking agents in guinea pig ventricular myocytes","endpoint":"APD90","system":"Whole-cell patch-clamped guinea-pig ventricular myocytes","exposure":"0.2–1 µM nisoldipine","claim":"Nisoldipine shortened APD90 without a lengthening phase.","locator":"Abstract, Results"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8371021/","title":"The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium","endpoint":"Baseline ventricular APD90","system":"Canine ventricular myocardium; 500-ms baseline cycle length","exposure":"1 µM nisoldipine; n=7","claim":"APD90 decreased from 187±5 to 159±5 ms, p<0.05, n=7.","locator":"Results, ICaL inhibition suppresses alternans; Figure 6"},{"url":"https://jci.org/articles/view/94996","title":"Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity","endpoint":"APD90","system":"Patient-derived human iPSC-CMs with severe familial LQT2","exposure":"0.05 µM nisoldipine","claim":"Nisoldipine shortened the prolonged APD90 in severely affected patient-derived cells toward the family-control value.","locator":"Figure 5 and Supplemental Table 4"}]},{"number":67,"display_number":65,"drug":"Paliperidone","studies":[77],"grade":"full","observed":"Modest clinical QTc prolongation in paliperidone thorough-QT testing.","predicted":"APD90 prolongation","reason":"Modeled prolongation agrees with directly measured QTc prolongation reported in the primary regulatory trial summary. The verdict is directional; the clinical QT effect was modest and does not calibrate the modeled APD90 magnitude.","limitations":"The positive 8-mg observation is from an immediate-release formulation, distinct from the extended-release comparator trial. No oral dose or single Cmax summary is fabricated into a model-matched free µM dose grid. Clinical QTcLD and cellular APD90 are different endpoints.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://www.medsafe.govt.nz/profs/datasheet/i/InvegaHafyerainj.pdf","title":"INVEGA HAFYERA data sheet: Effect on QT/QTc interval and cardiac electrophysiology","endpoint":"Placebo-subtracted QTcLD","system":"Double-blind active-controlled thorough-QT study in adults with schizophrenia/schizoaffective disorder; total n=141","exposure":"Immediate-release oral paliperidone 8 mg; n=50; day 8 at 1.5 hours post-dose; Cmax 113 ng/mL","claim":"Mean placebo-subtracted QTcLD increase was 12.3 ms (90% CI 8.9–15.6) for the 8-mg immediate-release dose.","locator":"Clinical pharmacology, Effect on QT/QTc interval and cardiac electrophysiology"},{"url":"https://pubmed.ncbi.nlm.nih.gov/20881844/","title":"Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study","endpoint":"QTcLD","system":"Randomized 109-patient clinical trial","exposure":"12 and 18 mg/day paliperidone ER versus quetiapine 800 mg/day and placebo","claim":"Primary additional QT study verifies testing at therapeutic and supratherapeutic paliperidone ER doses; it is an active-comparator noninferiority assessment rather than the source of the 12.3-ms immediate-release result.","locator":"Abstract, primary and secondary QT comparisons"}]},{"number":68,"display_number":66,"drug":"Paroxetine","studies":[78],"grade":"partial","observed":"Rare susceptible-patient QTc increases, but controlled studies show little QT effect and a guinea-pig experiment found APD90 shortening.","predicted":"APD90 prolongation","reason":"The small positive modeled response is compatible in direction with rare reported QTc increases, but does not capture the explicitly measured cellular APD90 shortening. Controlled clinical evidence was predominantly near-null; therefore this is mixed evidence and partial agreement, not a claim that paroxetine generally prolongs clinical QT or that a new no-effect threshold has been met.","limitations":"The observed 0.4-µM cellular shortening was at more than seven times the highest modeled concentration. The rare clinical QTc cases do not establish a general population trend, magnitude or a matched concentration. The clinical near-null result is not converted into confirmed positive prolongation or a retrospectively chosen success threshold. Peak voltage alone is not AP amplitude or maximum upstroke velocity; those endpoints are not interchanged.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[{"dose":0.4,"mean":-4.3,"sem":null,"n":null,"unit":"%","endpoint":"APD90 percent change","system":"Guinea-pig ventricular myocytes, 36°C, 5-min exposure","source":"Hong, Hwang and Jo 2018","url":"https://www.kci.go.kr/kciportal/ci/sereArticleSearch/ciSereArtiView.kci?sereArticleSearchBean.artiId=ART002329139","error_note":"Explicitly stated percentage in the primary abstract; n and uncertainty were not supplied and are not invented.","assay":"Guinea-pig ventricular myocytes, 36°C, 5-min exposure"}],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/9715482/","title":"[ECG changes after paroxetine. 3 case reports]","endpoint":"Clinical QTc","system":"Three high-risk clinical case reports","exposure":"Paroxetine treatment; quantitative exposure was not recoverable from abstract","claim":"QTc increased in two reported cases; the patients had a high-risk clinical profile.","locator":"Primary English abstract"},{"url":"https://www.kci.go.kr/kciportal/ci/sereArticleSearch/ciSereArtiView.kci?sereArticleSearchBean.artiId=ART002329139","title":"Effects of Paroxetine on a Human Ether-a-go-go-related Gene (hERG) K+ Channel Expressed in Xenopus Oocytes and on Cardiac Action Potential","endpoint":"APD90","system":"Guinea-pig ventricular myocytes at 36°C","exposure":"0.4 µM paroxetine for 5 minutes","claim":"The primary research abstract explicitly reports an APD90 decrease of 4.3%; hERG block alone is not substituted for this measured direction.","locator":"Primary article abstract; International Journal of Oral Biology 2018, 43(1):43–51, DOI 10.11620/ijob.2018.43.1.043"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41535245/","title":"An open-label, single-arm, dose-escalating concentration-QT study to investigate the cardiac effects and safety of paroxetine in healthy adults","endpoint":"QTcF versus plasma concentration","system":"38 healthy adults","exposure":"20, 40 and 60 mg/day, one week per dose level","claim":"The concentration-QTc analysis found no clinically significant effect; estimated maximum change was +0.42 ms with a 90% CI crossing zero at 60 mg/day.","locator":"Abstract, Results and Conclusions"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9915920/","title":"The Antidepressant Paroxetine Reduces the Cardiac Sodium Current","endpoint":"APD90, AP amplitude and maximum upstroke velocity","system":"Six isolated rabbit left-ventricular cardiomyocytes","exposure":"3 µM paroxetine; paced at 1 Hz","claim":"AP amplitude and upstroke velocity decreased, while APD20/50/90 did not change significantly.","locator":"Results section 2.2; Figure 4"}]},{"number":69,"display_number":67,"drug":"Pentobarbital","studies":[79],"grade":"full","observed":"Concentration-dependent ventricular APD prolongation and reduced upstroke velocity at anesthetic pentobarbital exposures.","predicted":"APD90 prolongation","reason":"The positive APD direction agrees with measured ventricular prolongation. The model response is very small and the published anesthetic exposures were higher; only direction is supported, not the experimental magnitude or an adequate clinical liability warning.","limitations":"APD95 is distinct from modeled APD90. Published concentrations are mg/L and have not been converted into µM without confirming the chemical-form basis. The modeled effect is orders smaller than the primary experiment's percentage changes; this verdict is qualitative only.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/2260699/","title":"Direct electrophysiological actions of pentobarbital at concentrations achieved during general anesthesia","endpoint":"APD95, effective refractory period and maximum upstroke velocity","system":"Guinea-pig papillary muscle and canine ventricular muscle","exposure":"Guinea pig: 25 and 50 mg/L; dog ventricular effects studied over 5–100 mg/L","claim":"Pentobarbital increased guinea-pig APD95 by 24±6% and 33±4% at 25/50 mg/L; dog ventricular APD also increased concentration-dependently.","locator":"Primary abstract, Results; DOI 10.1152/ajpheart.1990.259.6.H1743"}]},{"number":70,"display_number":68,"drug":"Phenytoin","studies":[80],"grade":"full","observed":"Published Purkinje-fiber plateau shortening","predicted":"APD90 shortening","reason":"The modeled shortening direction is consistent with experimentally observed action-potential plateau shortening.","limitations":"Published measurements describe plateau shortening in isolated calf/dog Purkinje fibers. CARDIX reports APD90 in adult human ventricular ORd cells. This supports qualitative direction without establishing equal APD90 magnitude or dose response. The modeled range overlaps the lower part of the 5–100 µM experimental range. The lowest model dose, 4.36 µM, is below the published range; 17.44 µM is the model maximum, not the published maximum of 100 µM.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/6861294/","title":"Scheuer and Kass 1983","endpoint":"Action-potential plateau phase and twitch tension","system":"Isolated calf and dog cardiac Purkinje fibers","exposure":"Electrical/mechanical measurements; two-microelectrode voltage clamp for ionic currents. Pacing, temperature and n were not specified in the abstract.","claim":"Lower/shorter plateau and reduced twitch tension","locator":"Abstract"}]},{"number":72,"display_number":69,"drug":"Prenylamine","studies":[82],"grade":"full","observed":"Clinical QT prolongation during prenylamine treatment, reversible after withdrawal.","predicted":"APD90 prolongation","reason":"The model captures the measured clinical prolongation direction. The primary comparison concerns QT duration, not a claim that the model has reproduced prenylamine-associated TdP.","limitations":"Clinical QT is distinct from cellular APD90. Oral treatment over weeks/months and free plasma concentrations are not the same as the 10-cycle model grid. The primary study did not observe serious arrhythmic events, so absent simulated EADs are not marked as a mismatch for this specific comparison.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2426055/","title":"The effect of prenylamine on the QT interval of the resting electrocardiogram in patients with angina pectoris","endpoint":"Resting ECG QT interval","system":"29 patients with angina pectoris followed before, during and after treatment","exposure":"Prenylamine 180 mg daily for up to 6 months","claim":"QT became significantly prolonged after one week, remained prolonged during treatment and returned to normal within two weeks of withdrawal.","locator":"Primary abstract and Results; DOI 10.1136/pgmj.56.661.753"}]},{"number":73,"display_number":70,"drug":"Primidone","studies":[83],"grade":"not_predicted","observed":"QT shortening and arrhythmia suppression during primidone treatment in a familial long-QT case series.","predicted":"APD90 prolongation","reason":"The model does not produce the reported shortening direction at any selected concentration. The source involved congenital long-QT patients and long-term treatment, whereas the simulation used a normal ventricular population and direct parent-drug channel scaling; this limits generalization of the mismatch.","limitations":"Small case series in congenital long-QT syndrome, not a controlled healthy-cell experiment. Long-term treatment and active metabolite contributions are not reproduced by a 10-cycle parent-drug ORd simulation. No clinical dose is converted into a fabricated µM graph point.","label":"Effect Not Captured","detail":"At tested model exposures","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/7396315/","title":"Primidone in the treatment of the long QT syndrome: QT shortening and ventricular arrhythmia suppression","endpoint":"QT interval and ventricular arrhythmia","system":"Three members of a family with long-QT syndrome","exposure":"Primidone therapy; index-case follow-up 2 years and two relatives followed for 8 months; quantitative dose/plasma concentration not recovered from abstract","claim":"Electrocardiographic and Holter recordings documented QT shortening during primidone treatment; ventricular arrhythmias were suppressed in the index case.","locator":"Primary abstract; DOI 10.7326/0003-4819-93-1-53"}]},{"number":74,"display_number":71,"drug":"Procainamide","studies":[84],"grade":"full","observed":"Clinical QTc prolongation and late ventricular APD prolongation at therapeutic procainamide exposure.","predicted":"APD90 prolongation","reason":"The model's prolongation direction agrees with measured QTc and late-repolarization APD changes. Effects on earlier repolarization and depolarization vary by preparation; the verdict does not claim those other endpoints were uniformly predicted.","limitations":"Clinical QTc, late APD100 and modeled APD90 are distinct endpoints. A reported serum concentration interval is not collapsed into an invented single experimental µM coordinate. The clinical parent drug/metabolite mix and protein binding differ from direct fixed-exposure cellular simulation.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://www.sciencedirect.com/science/article/pii/0002914986900251","title":"Effects of quinidine versus procainamide on the QT interval","endpoint":"QTc change from baseline","system":"18 patients receiving quinidine and procainamide separately","exposure":"Procainamide titrated to trough serum concentrations 4–12 µg/mL","claim":"Procainamide increased QTc by a reported mean 39±7 ms (SEM); its effect was smaller than quinidine's.","locator":"Primary abstract; DOI 10.1016/0002-9149(86)90025-1"},{"url":"https://pubmed.ncbi.nlm.nih.gov/2484078/","title":"Effects of therapeutic concentrations of procainamide on transmembrane action potentials of normal and infarct zone Purkinje fibers and ventricular muscle cells","endpoint":"Late APD100 and depolarization parameters","system":"Isolated canine Purkinje fibers and left-ventricular endocardial muscle","exposure":"10 mg/L procainamide","claim":"Procainamide increased APD100 in normal ventricular muscle and altered Purkinje APD in a preparation-dependent manner.","locator":"Abstract, Results"}]},{"number":75,"display_number":72,"drug":"Propafenone","studies":[85],"grade":"full","observed":"Ventricular APD90 prolongation and reduced action-potential amplitude","predicted":"APD90 prolongation","reason":"The modeled ventricular duration and peak-voltage directions agree with measured isolated ventricular-muscle effects. Purkinje-fiber shortening in the same article is a different cell preparation and is not represented by this ventricular-cell family.","limitations":"Direction comparison is restricted to the ventricular-muscle preparation. Purkinje behavior, conduction velocity and re-entry are outside the single-cell model. No numerical APD90 concentration-response values were recovered from the accessible primary abstract.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/7692158/","title":"Propafenone slows conduction and produces a nonuniform recovery of excitability between Purkinje and ventricular muscle fibers","endpoint":"APD90, action-potential amplitude, Vmax","system":"Isolated sheep ventricular muscle and Purkinje fibers","exposure":"0.1–1 µM; higher concentrations also examined","claim":"At 0.1–1 µM the drug reduced action-potential amplitude and Vmax; ventricular APD90 lengthened while Purkinje APD90 shortened.","locator":"Primary article abstract; DOI 10.1097/00005344-199308000-00005"}]},{"number":76,"display_number":73,"drug":"Propranolol","studies":[86],"grade":"not_predicted","observed":"Measured human ventricular APD / MAP90 shortening","predicted":"APD90 prolongation","reason":"The model's duration trend is opposite to measured concentration-dependent APD shortening in human papillary muscle and MAP90 shortening in patients. A modest model peak decrease does not reproduce the principal duration effect.","limitations":"Clinical MAP and isolated papillary-muscle APD are distinct preparations from an ORd cell. Clinical dose and tissue mass-concentration units are retained; no unsupported conversion to simulated free µM concentrations.","label":"Effect Not Captured","detail":"At tested model exposures","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/650893/","title":"Electrophysiologic effects of propranolol on the human heart","endpoint":"Action-potential duration, dV/dt, amplitude","system":"Human papillary muscle collected during cardiac surgery","exposure":"10^-9–10^-4 g/mL; APD shortening reported at 10^-8–10^-6 g/mL","claim":"Propranolol shortened APD concentration-dependently and lowered depolarization dV/dt; very high concentration also lowered amplitude.","locator":"Primary article abstract; DOI 10.1536/ihj.19.136"},{"url":"https://pubmed.ncbi.nlm.nih.gov/2253660/","title":"Effects of propranolol on ventricular repolarization in man","endpoint":"MAP90 at constant paced heart rate","system":"Ten patients with coronary artery disease","exposure":"0.2 mg/kg intravenous; pacing 100 beats/min","claim":"Median MAP90 shortened from 238 to 228 ms while ventricular effective refractory period remained unchanged.","locator":"Primary article abstract; DOI 10.1007/BF00280044"}]},{"number":77,"display_number":74,"drug":"Quetiapine","studies":[87],"grade":"full","observed":"QTcI prolongation in a controlled healthy-volunteer study","predicted":"APD90 prolongation","reason":"The positive modeled duration trend agrees qualitatively with measured clinical QTc prolongation. This is directional agreement, not agreement in effect magnitude or a same-endpoint validation.","limitations":"QTcI is a whole-heart clinical endpoint; CARDIX reports single-cell APD90. Oral 100 mg was not converted to µM. No numerical experimental points are placed on the model concentration axis.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/26950553/","title":"A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers","endpoint":"Placebo-adjusted change in QTcI","system":"Forty healthy volunteers; randomized four-period crossover","exposure":"Single oral quetiapine immediate-release 100 mg","claim":"Quetiapine produced a maximum mean QTcI increase of 10.2 ms, with an upper 95% confidence bound of 13.7 ms.","locator":"Abstract Results; DOI 10.1097/YIC.0000000000000124"}]},{"number":78,"display_number":75,"drug":"Quinine","studies":[88],"grade":"full","observed":"Measured QT prolongation in perfused hearts and controlled clinical dosing","predicted":"APD90 prolongation","reason":"The direction of model prolongation agrees with the positive measured QT response. The magnitude and exposure are not matched, and a separate antiarrhythmic patient study reported no QTc prolongation, illustrating preparation and protocol dependence.","limitations":"The selected positive observation concerns QT/QaTc, not human-cell APD90; the perfused-heart concentration range is below the simulated range. Separate human trial results were not uniformly positive. Agreement means reproduction of a documented prolonging direction, not consistency across all protocols. No numerical ECG dose-response values were digitized from figures.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2992072/","title":"Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system","endpoint":"QaT / corrected QaTc duration","system":"Isolated perfused guinea-pig hearts paced at 210 beats/min","exposure":"Quinine 0.3–2.4 µM","claim":"Quinine lengthened the measured ECG repolarization interval in the concentration-response assay.","locator":"Methods QT interval measurement and measured QT-prolongation results; DOI 10.1186/1475-2875-9-318"},{"url":"https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f567d5c7-ea5d-49a7-a035-b47208135f73&type=display","title":"Quinine sulfate prescribing information: controlled cardiac electrophysiology study","endpoint":"Baseline- and placebo-adjusted QTcI","system":"Young and elderly healthy subjects, 13 in each age group","exposure":"Quinine sulfate 648 mg three times daily for seven days","claim":"Maximum mean QTcI increase was 27.7 ms, with an upper 95% confidence bound of 32.2 ms.","locator":"Section 12.2 Pharmacodynamics"},{"url":"https://pubmed.ncbi.nlm.nih.gov/7586264/","title":"Antiarrhythmic activity of quinine in humans","endpoint":"QTc and ventricular refractoriness","system":"Patients with ventricular ectopy / inducible ventricular tachycardia","exposure":"Effective serum concentration mean 11 µM, range 4–17 µM in the first trial","claim":"The report found antiarrhythmic activity and refractory-period prolongation but did not find QTc prolongation.","locator":"Primary article abstract Results"}]},{"number":79,"display_number":76,"drug":"Raltegravir","studies":[89],"grade":"full","observed":"No QTcF prolongation in a supratherapeutic controlled study","predicted":"Minimal APD90 change","reason":"The nearly unchanged model duration and absence of suspected EADs agree with the negative thorough-QT finding. The <1 ms description is an internal descriptive rule, not a statistical or clinical threshold.","limitations":"Measured clinical total plasma Cmax is not identical to a protein-free model concentration. A negative QTcF result and a <1 ms model APD90 change are a qualitative comparison, not interchangeable quantitative endpoints.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/18441333/","title":"Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval","endpoint":"Placebo-adjusted QTcF change","system":"Healthy volunteers; randomized double-blind three-period crossover","exposure":"Single 1600 mg oral dose; measured mean total Cmax approximately 20 µM","claim":"Raltegravir did not prolong QTcF; the upper two-sided 90% confidence bound stayed below 10 ms at every assessed time.","locator":"Primary article abstract; DOI 10.1177/0091270008318007"}]},{"number":81,"display_number":77,"drug":"Ritonavir","studies":[91],"grade":"partial","observed":"Modest clinical QTc prolongation at high dosing; no effect or APD shortening in other measured protocols","predicted":"APD90 prolongation","reason":"The positive duration direction captures the modest high-dose clinical QTc signal, but not the negative 100 mg QT study or the opposite APD shortening measured in isolated rabbit cells. The result is mixed supporting evidence.","limitations":"Observed APD shortening is at a higher bath concentration than the model and involves a chloride-current mechanism outside standard ORd. QTcF and isolated APD90 are different endpoints; the clinical positive signal is modest and does not imply a positive regulatory thorough-QT result. The quantitative rabbit point must remain a separate endpoint/preparation series and must not be used as clinical QTc.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[{"dose":15,"mean":-60,"sem":9,"n":4,"system":"Rabbit ventricular myocytes","endpoint":"APD90 change","unit":"ms","assay":"15 min drug exposure","source":"Deng et al. 2010","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2988286/"}],"sources":[{"url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2f8c6ba-5e06-4b03-8ca5-b4fd7e5a8925","title":"Ritonavir prescribing information: cardiac electrophysiology","endpoint":"Placebo- and baseline-adjusted QTcF / PR changes","system":"Forty-five healthy adults; randomized active- and placebo-controlled crossover","exposure":"400 mg twice daily, assessed on day 3","claim":"The maximum mean QTcF increase was 5.5 ms, with an upper 95% confidence bound of 7.6 ms; PR also increased.","locator":"Section 12.2 Pharmacodynamics"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17581594/","title":"Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies","endpoint":"Placebo-adjusted QTcF change","system":"Sixty-five healthy volunteers; randomized crossover","exposure":"Single oral 100 mg","claim":"Maximum mean placebo-adjusted QTcF increase was 0.16 ms, with a 90% confidence interval from −1.38 to 1.69 ms; the study was negative.","locator":"Primary article abstract; DOI 10.1038/sj.clpt.6100263"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2988286/","title":"HIV protease inhibitors elicit volume-sensitive chloride current in cardiac myocytes via mitochondrial ROS","endpoint":"APD50, APD90","system":"Isolated rabbit ventricular myocytes","exposure":"Ritonavir 15 µM for 15 minutes","claim":"APD90 decreased by 60 ± 9 ms in four cells; the change was reversed by a volume-sensitive chloride-current blocker.","locator":"Section 3.5 and Figure 6; DOI 10.1016/j.yjmcc.2010.08.013"}]},{"number":82,"display_number":78,"drug":"Rufinamide","studies":[92],"grade":"full","observed":"Clinical QTc shortening during oral treatment","predicted":"APD90 shortening","reason":"The modeled repolarization-shortening direction is consistent with the published clinical QTc-shortening effect.","limitations":"Clinical QTc and single-cell APD90 are different endpoints. Directional consistency does not establish numerical equality, concentration equivalence or clinical safety. The primary abstract supplies no comparable free plasma or bath-concentration grid. No conversion from oral mg/day to modeled µM is assumed.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/22245794/","title":"Schimpf et al. 2012","endpoint":"Clinical QT/QTc intervals before and during oral therapy","system":"19 patients with difficult-to-treat epilepsies","exposure":"Before/during oral treatment. Figure 2 shows one patient at 2400 mg/day with concomitant antiepileptics; this is not an assay bath concentration.","claim":"QTc shortening","locator":"Abstract; Figure 2 caption"}]},{"number":83,"display_number":79,"drug":"Saquinavir","studies":[93],"grade":"partial","observed":"Dose-dependent QTc prolongation under ritonavir-boosted saquinavir dosing","predicted":"APD90 prolongation","reason":"The modeled prolongation direction agrees with the measured saquinavir-containing regimen. The experiment used ritonavir boosting, so attribution and exposure cannot be validated as saquinavir monotherapy.","limitations":"The observed regimen includes ritonavir, whereas this CARDIX study is saquinavir alone. The source's delayed/nonlinear clinical exposure-response is not represented by an acute ten-cycle fixed-concentration model. Oral dose was not mapped to simulated free µM concentrations.","label":"Relevant Effect Captured","detail":"Partial agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/21558456/","title":"Thorough QT/QTc study of ritonavir-boosted saquinavir following multiple-dose administration of therapeutic and supratherapeutic doses in healthy participants","endpoint":"Baseline- and placebo-adjusted study-specific QTc","system":"Healthy participants; randomized double-blind four-way crossover","exposure":"Saquinavir/ritonavir 1000/100 mg and 1500/100 mg twice daily","claim":"The greatest mean QTc increases were 18.9 and 30.2 ms for the therapeutic and supratherapeutic regimens.","locator":"Primary article abstract; DOI 10.1177/0091270011400071"},{"url":"https://www.fda.gov/media/84816/download","title":"FDA saquinavir clinical review: QT and PR study NP21249","endpoint":"QTc and PR","system":"Healthy-volunteer saquinavir/ritonavir study","exposure":"1000/100 mg and 1500/100 mg twice daily","claim":"The primary trial showed dose-dependent QTc and PR prolongation; QTc exposure-response was not linear and showed a delayed effect.","locator":"Section 6 Assessment of Safety, QT-study findings"}]},{"number":84,"display_number":80,"drug":"Sitagliptin","studies":[94],"grade":"full","observed":"No clinically meaningful QTcF prolongation; shallow concentration-response","predicted":"Minimal APD90 change","reason":"The model's minimal change agrees qualitatively with the controlled study's absence of clinically meaningful QT prolongation and shallow positive exposure-response.","limitations":"A <1 ms model APD90 description is not the clinical QTc decision threshold. The reported slope is a clinical pharmacokinetic-regression result, not an observed APD90 concentration point; it was not plotted as experimental samples.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/19602719/","title":"A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects","endpoint":"Placebo-adjusted QTcF change and concentration-QTc relationship","system":"Healthy volunteers; randomized double-blind four-period crossover","exposure":"Single oral 100 mg and 800 mg; 800 mg yielded approximately eleven-fold higher maximal concentrations","claim":"The clinical dose did not increase QTcF; the supratherapeutic dose produced only clinically insignificant prolongation, with a modeled slope of 0.59 ms per 1000 nM plasma concentration.","locator":"Primary article abstract; DOI 10.1177/0091270009337511"}]},{"number":85,"display_number":81,"drug":"Solifenacin","studies":[95],"grade":"full","observed":"Small dose-related QTcF increases in a controlled clinical study","predicted":"APD90 prolongation","reason":"The positive model duration trend agrees with the small dose-related measured QTcF response. This comparison is qualitative and does not equate oral dosing with model concentration.","limitations":"QTcF is a clinical endpoint, not the same measurement as model APD90. No numerical clinical points were assigned to unverified free µM concentrations.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021518s007lbl.pdf","title":"VESIcare prescribing information: cardiac electrophysiology trial","endpoint":"Placebo-adjusted QTcF at Tmax","system":"Seventy-six healthy women; multidose randomized active- and placebo-controlled study","exposure":"Solifenacin 10 mg and 30 mg","claim":"Mean QTcF changes were 2 ms (90% CI −3 to 6) and 8 ms (90% CI 4 to 13) at 10 and 30 mg; higher-dose prolongation exceeded the lower-dose effect.","locator":"Cardiac Electrophysiology and Table 1, printed page 4"},{"url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=70fece2c-a59f-43f9-abbf-ac67500e90bb","title":"Solifenacin succinate prescribing information: QT prolongation","endpoint":"QTcF","system":"Seventy-six healthy women","exposure":"30 mg, three times the maximum adult dose","claim":"The controlled mean QTcF increase was 8 ms with 90% CI 4–13, and the prolonging effect was smaller at 10 mg.","locator":"Sections 5.6 and 12.2"}]},{"number":86,"display_number":82,"drug":"Sunitinib","studies":[96],"grade":"full","observed":"Exposure-related QTcF prolongation in cancer patients","predicted":"APD90 prolongation","reason":"Modeled duration increases with concentration, agreeing with the measured exposure-related QTcF direction. The model does not reproduce cancer-patient physiology, metabolite contributions or clinical effect magnitude.","limitations":"Clinical measurements include active-metabolite exposure and patient covariates; this CARDIX study uses parent-drug fixed free concentrations. Oral loading/maintenance regimens were not converted to model µM points.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/19903787/","title":"Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic-pharmacodynamic evaluation of sunitinib","endpoint":"Time-matched placebo-adjusted QTcF","system":"Cancer patients; 24 of 48 were QT/PK evaluable","exposure":"Loading 150–200 mg on days 3 and 9; maintenance 50 mg/day on days 4–8","claim":"QTcF changes increased with exposure. Maximum mean changes were 9.6 ms (90% CI 4.1–15.1) at therapeutic exposure and 15.4 ms (8.4–22.4) at supratherapeutic exposure.","locator":"Primary article abstract Results; DOI 10.1158/1078-0432.CCR-09-1521"}]},{"number":87,"display_number":83,"drug":"Tedisamil","studies":[97],"grade":"full","observed":"Human ventricular MAP90 / QTc and isolated ventricular APD prolongation","predicted":"APD90 prolongation","reason":"The modeled duration direction agrees with measured human ventricular repolarization prolongation and isolated ventricular-muscle observations.","limitations":"The clinical dose and reported isolated-fiber dose do not match the exact simulated concentration grid. This verdict addresses duration direction; it does not claim the model reproduces human TdP or all rate-dependent mechanisms.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/7821321/","title":"Prolongation of monophasic action potential duration and the refractory period in the human heart by tedisamil, a new potassium-blocking agent","endpoint":"MAP90, QTc","system":"Ten patients with coronary artery disease; atrial pacing at multiple cycle lengths","exposure":"0.3 mg/kg intravenous","claim":"QTc lengthened by about 10% and ventricular MAP90 by about 16%; prolongation persisted during constant-rate pacing.","locator":"Primary article abstract; DOI 10.1093/oxfordjournals.eurheartj.a060403"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10684468/","title":"Frequency-dependent cardiac electrophysiologic effects of tedisamil: comparison with quinidine and sotalol","endpoint":"AP duration","system":"Isolated dog ventricular muscle / Purkinje fibers and rabbit atrial muscle","exposure":"Tedisamil 1 µM in reported Purkinje comparison","claim":"Tedisamil lengthened repolarization in ventricular muscle and Purkinje fibers, with preparation-dependent frequency effects.","locator":"Primary article abstract Methods and Results"}]},{"number":88,"display_number":84,"drug":"Telbivudine","studies":[98],"grade":"not_predicted","observed":"Negative clinical QT study with no concentration-related QTcF increase","predicted":"APD90 prolongation","reason":"The monotonic model duration increase does not reproduce the controlled study's lack of QTcF prolongation or concentration-related trend. APD90 and QTcF are different endpoints, so the mismatch is qualitative rather than a clinical-threshold comparison.","limitations":"No clinical mean per-dose values or matched free-plasma µM observations were recovered; no artificial zero-valued points were plotted. The discrepancy may reflect the supplied ion-channel input profile and does not establish clinical proarrhythmia.","label":"Effect Not Captured","detail":"At tested model exposures","observed_points":[],"sources":[{"url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/22011s000_ClinPharmR.pdf","title":"FDA telbivudine clinical pharmacology review","endpoint":"Thorough QT / QTcF","system":"Healthy volunteers; placebo- and positive-controlled study","exposure":"Telbivudine 600 mg/day and 1800 mg/day","claim":"Both clinical and supratherapeutic doses met the criterion for a negative thorough-QT study; moxifloxacin was positive.","locator":"Section 2.2.4.3, Does this drug prolong the QT or QTc interval?"},{"url":"https://www.ema.europa.eu/en/documents/variation-report/sebivo-h-c-713-r-0023-epar-assessment-report-renewal_en.pdf","title":"EMA Sebivo renewal assessment report","endpoint":"QTcF and concentration-response","system":"Healthy volunteers in telbivudine QT study","exposure":"600 mg and 1800 mg","claim":"QTcF changes did not exceed 5 ms, upper one-sided 95% confidence bounds did not exceed 10 ms, and QTcF did not increase with plasma telbivudine.","locator":"Cardiac safety / QTc study summary"}]},{"number":89,"display_number":85,"drug":"Terodiline","studies":[99],"grade":"full","observed":"Concentration-dependent QTc prolongation in treated patients","predicted":"APD90 prolongation","reason":"The model prolongs duration with concentration, agreeing with the measured clinical QTc concentration relationship. Absence of model EADs does not validate or negate clinically observed TdP.","limitations":"Clinical total plasma and stereoselective exposure are different from fixed model free concentrations. The report's QTc units and correction were retained as clinical QTc; no conversion into cellular APD90 measurements.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/7662454/","title":"Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence","endpoint":"QTc and QT dispersion","system":"Twelve treated patients in sinus rhythm with on/off-drug ECG comparisons","exposure":"Stable oral treatment; measured total plasma parent and enantiomers","claim":"Mean QTc increased from 443 to 491 ms during treatment; mean drug-induced increase was 48 ms with a 95% interval of 23–74. QTc change correlated with total plasma concentration.","locator":"Primary article abstract Results; DOI 10.1136/hrt.74.1.53"},{"url":"https://pubmed.ncbi.nlm.nih.gov/8689817/","title":"Stereoselective cardiotoxic effects of terodiline","endpoint":"QTc","system":"Nine healthy volunteers; randomized double-blind crossover","exposure":"Racemic terodiline hydrochloride 200 mg and individual enantiomers","claim":"Racemic and R(+)-terodiline increased QTc; the S(−) enantiomer did not. Peak mean change with racemate was 23 ms at eight hours.","locator":"Primary article abstract Results"}]},{"number":90,"display_number":86,"drug":"Thioridazine","studies":[100],"grade":"full","observed":"Published MAPD / APD prolongation and reported EADs","predicted":"APD90 prolongation","reason":"Modeled APD prolongation and suspected EADs are consistent in direction with published experimental repolarization prolongation and EAD observations.","limitations":"Drolet1999 used guinea-pig hearts paced at 150–250 ms, whereas CARDIX uses adult human ventricular ORd at 1000 ms. Liu2020 used chronic 24 h hiPSC exposure and mouse hearts; chronic ROS/protein-loss/calcium-channel activation mechanisms and clinical TdP are not reproduced by static inhibition. Most modeled doses overlap the published 0.3–3 µM range; 3.92 µM exceeds its upper bound. The modeled 2.94 µM point is near, but not identical to, the separate 3 µM hiPSC exposure.","label":"Effect Predicted","detail":"Qualitative agreement","review_origin":"supporting_literature","sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/10027867/","title":"Drolet et al. 1999","endpoint":"Monophasic action-potential duration at 90% repolarization (MAPD90)","system":"32 isolated buffer-perfused guinea-pig hearts","exposure":"Pacing cycle lengths 150–250 ms; greater prolongation at slower pacing.","claim":"Concentration-dependent prolongation","locator":"Abstract"},{"url":"https://pubmed.ncbi.nlm.nih.gov/32064022/","title":"Liu et al. 2020","endpoint":"APD50/APD90; EADs in mouse hearts","system":"Mouse hearts and human induced pluripotent stem cell cardiomyocytes","exposure":"hiPSC-CM current clamp after 24 h exposure at 3 µM, n=5–8; mouse-heart optical mapping, n=5.","claim":"APD prolongation; increased EAD occurrence in mouse hearts","locator":"Abstract and Figure 8 caption"}]},{"number":91,"display_number":87,"drug":"Toremifene","studies":[101],"grade":"full","observed":"Dose- and concentration-related clinical QTc prolongation","predicted":"APD90 prolongation","reason":"The positive model duration trend agrees with controlled clinical dose-related QTc prolongation; the much larger observed QTc magnitude is not claimed as quantitatively reproduced.","limitations":"Parent and N-demethyl metabolite contribute clinically; model uses a fixed parent-drug profile. No unsupported oral dose-to-free-µM mapping was used for numerical experimental plotting.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[],"sources":[{"url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2cab8dd1-3a10-48e6-86ce-0e5275ed49e5","title":"FARESTON prescribing information: QTc prolongation in healthy male volunteers","endpoint":"Placebo- and baseline-adjusted QTc","system":"Healthy men aged 18–45; randomized double-blind parallel study","exposure":"20, 80 and 300 mg; day 5","claim":"Mean QTc increases were 7, 26 and 65 ms at 20, 80 and 300 mg; effects were dose- and concentration-related.","locator":"Section 12.2, Effects on Cardiac Electrophysiology, Table 1"},{"url":"https://www.ema.europa.eu/en/documents/product-information/fareston-epar-product-information_en.pdf","title":"Fareston product information: clinical QT study","endpoint":"QTc","system":"Five-arm clinical QT study with 250 male participants","exposure":"20, 80 and 300 mg toremifene, moxifloxacin and placebo","claim":"The measured QTc response showed a dose-dependent prolonging effect, with a clear positive effect in the 80 mg group.","locator":"Section 4.4, QT clinical study"}]},{"number":92,"display_number":88,"drug":"Voriconazole","studies":[102],"grade":"full","observed":"Rabbit whole-heart QT prolongation without EADs","predicted":"APD90 prolongation","reason":"The positive duration direction and absence of EADs agree with measured voriconazole-treated rabbit hearts. The experimental 30 µM concentration lies close to the model's highest dose; magnitude equality is not claimed.","limitations":"Observed numeric values are QT changes, not APD90 values; they remain labeled as such. No numerical value was invented for 10 µM, for which the accessible abstract did not give a QT-change value. Failure to elicit EADs in one model or protocol is not a clinical safety guarantee.","label":"Effect Predicted","detail":"Qualitative agreement","observed_points":[{"dose":30,"mean":10,"sem":null,"n":6,"system":"Isolated female rabbit whole hearts","endpoint":"QT change","unit":"ms","assay":"Whole-heart ECG","source":"Frommeyer et al. 2016","url":"https://pubmed.ncbi.nlm.nih.gov/26905475/"},{"dose":50,"mean":20,"sem":null,"n":6,"system":"Isolated female rabbit whole hearts","endpoint":"QT change","unit":"ms","assay":"Whole-heart ECG","source":"Frommeyer et al. 2016","url":"https://pubmed.ncbi.nlm.nih.gov/26905475/"}],"sources":[{"url":"https://pubmed.ncbi.nlm.nih.gov/26905475/","title":"Divergent electrophysiologic profile of fluconazole and voriconazole in an experimental whole-heart model of proarrhythmia","endpoint":"QT and EAD / polymorphic ventricular tachycardia occurrence","system":"Isolated female rabbit whole hearts, six per drug","exposure":"Voriconazole 10, 30 and 50 µM; additional hypokalemia/bradycardic challenge","claim":"Voriconazole prolonged QT by 10 ms at 30 µM and 20 ms at 50 µM. No EADs or polymorphic ventricular tachycardia were induced in voriconazole-treated hearts during the sensitizing challenge.","locator":"Primary article abstract Results; DOI 10.1016/j.ejphar.2016.02.051"},{"url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3af8cfe6-1c0d-4b57-ae31-05cffa64132e","title":"Voriconazole prescribing information: cardiac electrophysiology","endpoint":"Placebo-adjusted QTc","system":"Healthy men and women; randomized crossover","exposure":"Single oral 800, 1200 and 1600 mg","claim":"Mean maximal QTc increases were below 10 ms at all tested doses, with no QTc above 500 ms or increase at least 60 ms.","locator":"Cardiac Electrophysiology section"}]}]},"plot_review":[{"number":1,"display_number":1,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":2,"display_number":2,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":3,"display_number":3,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":4,"display_number":4,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":5,"display_number":5,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":6,"display_number":6,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":7,"display_number":7,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":8,"display_number":8,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":9,"display_number":9,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":10,"display_number":10,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":11,"display_number":11,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":12,"display_number":12,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":13,"display_number":13,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":14,"display_number":14,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":15,"display_number":15,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":16,"display_number":16,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":"Initial shortening is captured; the later concentration-response trend differs."},{"number":17,"display_number":17,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":18,"display_number":18,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":19,"display_number":19,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":20,"display_number":20,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":21,"display_number":21,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":22,"display_number":22,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":23,"display_number":23,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":24,"display_number":24,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":25,"display_number":25,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":26,"display_number":26,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":27,"display_number":27,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":28,"display_number":28,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":29,"display_number":29,"evidence_type":"categorical_event","no_points_reason":"The comparison uses Huo Table 1 EAD-like event presence at MEC-EAD 0.1 µM. FPDc and arrhythmic-well curves exist in Figures 3/4 but were not extracted for this event comparison.","card_note":""},{"number":30,"display_number":30,"evidence_type":"categorical_event","no_points_reason":"The comparison uses Huo Table 1 EAD-like event presence at MEC-EAD 30 µM. FPDc and arrhythmic-well curves exist in Figures 3/4 but were not extracted for this event comparison.","card_note":""},{"number":31,"display_number":31,"evidence_type":"categorical_event","no_points_reason":"The comparison uses Huo Table 1 EAD-like event presence at MEC-EAD 30 µM. FPDc and arrhythmic-well curves exist in Figures 3/4 but were not extracted for this event comparison.","card_note":""},{"number":32,"display_number":32,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":33,"display_number":33,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":34,"display_number":34,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":35,"display_number":35,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":36,"display_number":36,"evidence_type":"experimental_values_not_extracted","no_points_reason":"Native ventricular and donor hiPSC experiments support the stated direction; numerical concentration–duration pairs were not extracted from the selected sources. The preparations have different responses.","card_note":""},{"number":37,"display_number":37,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Human APD90 measurements followed loading/chronic treatment. Administered mg/day and metabolite exposure were not converted into a common free-µM concentration axis.","card_note":""},{"number":38,"display_number":38,"evidence_type":"mixed_preparations_values_not_extracted","no_points_reason":"Primary experiments describe a biphasic APD response and a separate toxic infusion protocol. Exact dose–duration pairs were not extracted; mg/kg/min is not bath µM.","card_note":""},{"number":39,"display_number":39,"evidence_type":"mixed_clinical_experimental_values_not_extracted","no_points_reason":"Measured clinical QT associations and a high-exposure controlled guinea-pig ECG/APD study support prolongation. No verified concentration–duration pairs from those studies were extracted for the plot.","card_note":""},{"number":41,"display_number":40,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The primary abstract reports concentration-dependent APD prolongation at 0.3–10 µM, but numerical APD90 values per concentration were not extracted.","card_note":""},{"number":42,"display_number":41,"evidence_type":"experimental_values_not_extracted","no_points_reason":"Dog and guinea-pig experiments have differing APD responses. Their numerical concentration–duration curves were not extracted or merged into an artificial single series.","card_note":""},{"number":43,"display_number":42,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QTc was measured after 100 mg twice daily for three months. Oral dosing was not converted into fixed free-µM points for the ten-cycle cellular model.","card_note":""},{"number":44,"display_number":43,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"The clinical QTc change applies to affected cases, not all administrations. No matched free-µM concentration–response samples were recovered.","card_note":""},{"number":45,"display_number":44,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The selected primary study reports acute/chronic APD prolongation at 1 and 10 µM. Numerical duration values were not extracted; APD100 and APD90 are distinct.","card_note":""},{"number":46,"display_number":45,"evidence_type":"experimental_null_without_extracted_samples","no_points_reason":"The selected experiment reports no APD prolongation with diazepam alone at 1 µM. Exact numerical samples were not extracted; an artificial zero-response point was not created.","card_note":""},{"number":47,"display_number":46,"evidence_type":"mixed_clinical_experimental_values_not_extracted","no_points_reason":"Clinical QTc and experimental MAPD lengthening are reported, but comparable concentration–duration samples were not extracted. Total clinical plasma and nominal bath concentrations are not interchangeable.","card_note":""},{"number":48,"display_number":47,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"ECG cohorts report QT/QTc measurements under oral treatment, with heterogeneous findings. No verified free-µM concentration–outcome pairs were extracted.","card_note":""},{"number":49,"display_number":48,"evidence_type":"clinical_null_without_matched_samples","no_points_reason":"The controlled thorough-QT study found no QT prolongation at oral doses up to 200 mg twice daily. No measured free-µM samples were mapped to this graph, and no zero points were fabricated.","card_note":""},{"number":50,"display_number":49,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":51,"display_number":50,"evidence_type":"experimental_administered_dose_not_concentration","no_points_reason":"The selected in-vivo study measured QTc after systemic infusion. Infusion doses were not converted into bath/free-µM concentrations; numerical concentration–QTc pairs were not extracted.","card_note":""},{"number":52,"display_number":51,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical concentration-related QTc prolongation is reported, but individual comparable concentration–QTc pairs were not extracted. Stereoselective total/free exposure and malaria physiology remain distinct.","card_note":""},{"number":53,"display_number":52,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The selected studies describe measured APD prolongation and a biphasic response. Numerical curve values were not extracted; the 3 µM example is far above the simulated range.","card_note":""},{"number":54,"display_number":53,"evidence_type":"mixed_preparations_values_not_extracted","no_points_reason":"Systemic QTc prolongation and cellular/Purkinje APD shortening occur in different preparations. Exact concentration–duration series were not extracted or pooled.","card_note":""},{"number":56,"display_number":54,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":57,"display_number":55,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"The controlled study contains clinical QTcF time-course data after 600/1200 mg dosing. These administered doses were not converted into a model free-µM concentration grid.","card_note":""},{"number":58,"display_number":56,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":59,"display_number":57,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QTc measurements followed maintenance treatment. Administered oral dose, chronic exposure and patient pharmacokinetics were not converted into matched free-µM samples.","card_note":""},{"number":60,"display_number":58,"evidence_type":"clinical_case_no_measured_concentration","no_points_reason":"The case report contains measured QTc before/after IV treatment and withdrawal but no recoverable plasma concentration. No concentration–response coordinate was fabricated.","card_note":""},{"number":61,"display_number":59,"evidence_type":"mixed_preparations_values_not_extracted","no_points_reason":"The source reports cell AP plateau shortening and whole-heart MAP/QT results in several species. A complete numerical cellular concentration grid was not recovered.","card_note":""},{"number":62,"display_number":60,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The source reports APD prolongation and occasional EADs at 30 µM. Numerical APD changes and EAD incidence were not extracted; the modeled concentrations are much lower.","card_note":""},{"number":63,"display_number":61,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":64,"display_number":62,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical exposure–QTcF relationships exist, but individual numerical free-concentration–response pairs were not extracted. Total serum, metabolite and patient context differ from the model.","card_note":""},{"number":65,"display_number":63,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":66,"display_number":64,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":67,"display_number":65,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QTc results are reported for oral formulations/doses. No verified mapping from administered mg or a single Cmax summary to the modeled free-µM dose grid was made.","card_note":""},{"number":68,"display_number":66,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":69,"display_number":67,"evidence_type":"mass_concentration_chemical_basis_unresolved","no_points_reason":"Numerical APD95 changes are reported at 25/50 mg/L. The chemical-form basis was not confirmed for a µM conversion; APD95 is also distinct from model APD90.","card_note":""},{"number":70,"display_number":68,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The primary source reports Purkinje plateau shortening across 5–100 µM. Numerical duration values for individual concentrations were not extracted; plateau and ventricular APD90 are different endpoints.","card_note":""},{"number":72,"display_number":69,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QT was measured during treatment and after withdrawal. Oral treatment was not converted into acute fixed free-µM coordinates.","card_note":""},{"number":73,"display_number":70,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"A familial long-QT case series reports QT shortening during long-term treatment. No comparable parent-drug free-µM samples were recovered; active metabolites are not modeled.","card_note":""},{"number":74,"display_number":71,"evidence_type":"mixed_clinical_experimental_values_not_extracted","no_points_reason":"Clinical QTc and late APD data exist. A serum concentration interval was not collapsed into an invented single free-µM coordinate; numeric individual concentration–duration pairs were not extracted.","card_note":""},{"number":75,"display_number":72,"evidence_type":"experimental_values_not_extracted","no_points_reason":"The accessible primary abstract reports ventricular APD90 prolongation and amplitude reduction at 0.1–1 µM, but no numerical APD90 values per concentration were recovered.","card_note":""},{"number":76,"display_number":73,"evidence_type":"mixed_clinical_mass_dose_not_common_concentration","no_points_reason":"Human MAP90 and papillary-muscle APD measurements support shortening. Clinical mg/kg and tissue mass-concentration dosing were not converted into unverified free-µM samples.","card_note":""},{"number":77,"display_number":74,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"The controlled study reports QTcI after 100 mg oral dosing, including a numerical QTc increase. Oral mg was not converted into model concentration points.","card_note":""},{"number":78,"display_number":75,"evidence_type":"mixed_clinical_experimental_values_not_extracted","no_points_reason":"Perfused-heart QaTc concentration curves exist and clinical QT measurements are reported. Exact ECG curve values were not digitized or extracted; oral dose was not converted into µM.","card_note":""},{"number":79,"display_number":76,"evidence_type":"clinical_null_without_matched_samples","no_points_reason":"The supratherapeutic controlled study found no QTcF prolongation. A total-plasma Cmax summary is not a set of paired free-concentration–response samples; zero-response points were not invented.","card_note":""},{"number":81,"display_number":77,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""},{"number":82,"display_number":78,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QTc shortening is numerically reported during oral treatment. The source supplies no comparable free-plasma or bath-concentration grid; mg/day was not converted to µM.","card_note":""},{"number":83,"display_number":79,"evidence_type":"combination_clinical_dose_not_common_concentration","no_points_reason":"Numerical QTc responses follow saquinavir/ritonavir oral regimens. They are not isolated saquinavir bath/free-µM measurements; dose contrasts retain ritonavir and pharmacokinetic attribution limits.","card_note":""},{"number":84,"display_number":80,"evidence_type":"clinical_null_or_regression_not_observed_samples","no_points_reason":"The source reports no clinically meaningful QTcF prolongation and a shallow clinical concentration–QTc regression. Regression slopes were not turned into invented observed APD90 samples.","card_note":""},{"number":85,"display_number":81,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"The clinical study reports numerical QTcF changes at 10/30 mg oral dosing. No verified free-µM coordinates were assigned to those doses.","card_note":""},{"number":86,"display_number":82,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical QTcF measurements followed loading/maintenance dosing and include metabolite exposure. Oral regimens were not converted into parent-drug fixed free-µM samples.","card_note":""},{"number":87,"display_number":83,"evidence_type":"mixed_clinical_experimental_values_not_extracted","no_points_reason":"Clinical MAP90/QTc and isolated-fiber APD measurements exist, but numerical concentration–duration pairs for a common µM axis were not extracted; clinical mg/kg is not bath µM.","card_note":""},{"number":88,"display_number":84,"evidence_type":"clinical_null_without_matched_samples","no_points_reason":"Clinical QT testing found no concentration-related QTcF increase. Per-dose mean/free-plasma observations were not recovered, so zero-valued points were not fabricated.","card_note":""},{"number":89,"display_number":85,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Clinical total-plasma concentration–QTc relations exist but individual comparable numerical pairs were not extracted. Stereoselective and free/total exposure differences were retained.","card_note":""},{"number":90,"display_number":86,"evidence_type":"experimental_values_not_extracted","no_points_reason":"Primary sources report MAPD/APD prolongation and EADs at 0.3–3 µM or after chronic exposure. Numerical duration curves and event incidence were not extracted or pooled across preparations.","card_note":""},{"number":91,"display_number":87,"evidence_type":"clinical_values_no_common_concentration","no_points_reason":"Numerical clinical QTc changes follow 20/80/300 mg dosing and include metabolite contributions. Oral doses were not converted into unverified free-µM observations.","card_note":""},{"number":92,"display_number":88,"evidence_type":"numeric_concentration_outcome","no_points_reason":null,"card_note":""}],"public_data_scope":"Reviewed scientific observations and aggregate model outputs. No local paths, configurations, conductance arrays, raw model states or credentials are included."}