This is the first study of its kind to examine the effects of 30 clinical drugs against the seven ion currents currently proposed to makeup the CiPA ion channel panel. The results indicate the importance of drug-induced block of hERG, Nav1.5-late and Cav1.2 at clinically relevant concentrations, with low risk torsade drugs having equal or greater Nav1.5-late or Cav1.2 block compared to hERG block. In addition, the results of this study provide data which can be used to test the ability of various in silico models to predict drug-induced arrhythmias.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

Background--Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology.Methods and Results--Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At predose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide).Conclusions--T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. Long QT syndrome patients are at increased risk for torsade de pointes, a potentially fatal ventricular arrhythmia.2 Conventionally, physicians and drug regulators have focused solely on the QT interval in assessing risk for torsade; however, more information may be present in the electrocardiogram (ECG). Moss and colleagues 3 identified different T wave patterns associated with the 3 major congenital long QT syndrome types. LQT1 patients (decreased IKs current) have early onset broad-based T waves, LQT2 patients (decreased hERG potassium current, IKr) have low amplitude, bifid or notched T waves, and LQT3 patients (increased late sodium current, INa late ) have long isoelectric ST segments with lateappearing, normal morphology T waves. In the 1990s, there was recognition of an epidemic of druginduced QT prolongation and torsade de pointes resulting in many drugs being withdrawn from the market. 4 It was also recognized that nearly all drugs that increased torsade risk blocked the hERG potassium channel. 5 This resulted in all new drugs being required to be screened for their ability to block the hERG potassium channel and prolong QT in Thorough QT studies. 6,7 However, the extreme focus on hERG and QT has There are multiple examples of drugs on the market that block the hERG channel (an outward potassium current), but ...

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-T peak (J-T peak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from Correspondence: DG Strauss David.Strauss@fda.hhs.gov. Additional Supporting Information may be found in the online version of this article.Author Contributions: All authors have contributed as follows: protocol development (L.J., J.V., J.W.M., C.S., K.W.L., J.F., N.S., D.G.S.), data collection (C.E., C.S., K.W.L., M.H., J.L., P.G., A.M., J.W., W.J.C.), data analysis (L.J., J.V., J.F., D.G.S.), and preparing the manuscript (L.J., D.G.S.). All authors discussed the results and implications and commented on the manuscript. Conflict of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript hERG potassium channel block and assessment of J-T peak c may add value beyond only assessing QTc.Drug-induced QT prolongation increases the risk for torsade de pointes, a potentially fatal ventricular arrhythmia. 1 QT prolongation and increased risk for torsade de pointes have resulted in 14 drugs being removed from the market worldwide. 2 Furthermore, many drugs remain on the market with a known torsade de pointes risk, including numerous antibiotics, antimalarial, antiviral, psychiatric, oncology, and cardiac drugs. 3 At the same time, the current regulatory paradigm for assessing drug effects on cardiac repolarization is preventing potentially effective medicines from reaching the market, sometimes inappropriately. 2 To address this, the US Food and Drug Administration (FDA) and multiple public-private partnerships are studying novel approaches to assess the cardiac safety of new drugs with a Comprehensive in vitro Proarrhythmia Assay and in Phase 1 clinical trials. 4,5 Essential to the novel approaches is a focus on understanding mechanisms by studying the effects of drugs on multiple cardiac ion channels, which can be either proarrhythmic or antiarrhythmic depending on the combination. 6Almost all drugs on the market that can cause torsade de pointes block the hERG potassium channel 7 and prolong the QT interval of the electrocardiogram (ECG). 8 However, some drugs block the hERG potassium channel and prolong QT with a minimal torsade de pointes risk (e....

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic‐based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell‐derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J‐Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.