Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study

Jose Vicente, Robbert Zusterzeel, Lars Johannesen, Jay Mason, Philip Sager, Vikram Patel, Murali K Matta, Zhihua Li, Jiang Liu, Christine Garnett, Norman Stockbridge, Issam Zineh, David G Strauss, Jose Vicente, Robbert Zusterzeel, Lars Johannesen, Jay Mason, Philip Sager, Vikram Patel, Murali K Matta, Zhihua Li, Jiang Liu, Christine Garnett, Norman Stockbridge, Issam Zineh, David G Strauss

Abstract

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.

© 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Potential impact of CiPA on early and late drug development. (a) Top, left panel shows current ICH S7B nonclinical testing strategy. (b) Under CiPA, early assessment of drug effects on multiple ion channels using high‐throughput systems coupled with the in silico model predictions and outcomes from human induced pluripotent stem cell (iPSC) derived cardiomyocytes assays could inform lead identification/optimization, candidate drug selection, and the current ICH S7B strategy, in particular for drugs with hERG block and/or QTc prolongation. (c) Top, right panel shows current ICH E14 ECG monitoring considerations for QTc prolonging drugs in clinical development. Intensity of ECG monitoring depends on pharmacokinetic characteristics, patient characteristics, and adverse events that increase proarrhythmic risk. (d) CiPA's mechanistic approach will provide additional information that could influence this ECG monitoring decision process and drug labeling (see FDA advisory committee9 responses to questions in the text). Top, left panel diagram A adapted from ICH S7B guideline.2 Top, right panel diagram C depicts examples described in ICH E14 Questions & Answers Document in Section 7 (Electrocardiograms Monitoring in Late Stage Clinical Trials).4 ΔΔQTc, QTc placebo adjusted change from baseline.
Figure 2
Figure 2
Effect of predominant hERG potassium channel block vs. balanced ion channel block on QT prolongation and generation of torsade de pointes. Illustration of predominant hERG block leading to torsade de pointes (left column) vs. balanced ion channel block causing QT prolongation without torsade de pointes (right column). Predominant hERG block reduces the hERG potassium channel current (panel a), which delays repolarization and prolongs the action potential duration of cardiomyocytes (panel b, red dotted line) and the QT interval on the ECG (panel c, red dotted line). Prolonged repolarization can result in early afterdepolarizations (panel b, red solid line), which are caused by inward currents through sodium and calcium channels11 (panel a, purple and yellow arrows) and can trigger torsade de pointes (panel c, solid red line). In addition to causing hERG block, balanced ion channel‐blocking drugs block the L‐type calcium and/or late sodium currents (panel d). While balanced ion channel block can prolong both the action potential duration of cadiomyocytes (panel e) and the QT interval on the ECG (panel f), the block of inward currents (calcium, late sodium) prevents the occurrence of early afterdepolarizations and has antiarrhythmic effects.11, 12, 13, 14, 15, 16, 17, 18 In addition, balanced ion channel block causes different morphology changes in the action potential (panel e, red solid line) and the ECG (panel f, red solid line) than predominant hERG block (panels b and c, respectively). The goal of the CiPA phase I ECG validation study described in this article is to show that exposure–response ECG analysis can differentiate predominant hERG‐blocking drugs from balanced ion channel‐blocking drugs. Na, sodium ions; Ca, calcium ions; K, potassium ions.
Figure 3
Figure 3
The four components of the Comprehensive in vitro Proarrhythmia Assay (CiPA). Illustration of the four components of the CiPA initiative. First, drug effects on multiple ion channel currents are assessed. Second, a proarrhythmic score is computed using an in silico model of the human ventricular cardiomyocyte, which integrates the individual ion channel effects assessed in the first component. The third component is a confirmatory in vitro study using human stem cell‐derived ventricular cardiomyocytes. The goal of component four is to use human phase I ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data.60
Figure 4
Figure 4
In silico proarrhythmia risk categorization of the 12 CiPA training set drugs. Mechanistic proarrhythmic prediction from the in silico cardiomyocyte model indicating how close a drug is to generating an early afterdepolarization, the trigger for torsade de pointes. The X axis indicates drug concentration in multiples of clinical Cmax for each drug separately (e.g., 1‐fold Cmax, 2‐fold Cmax, etc., up to 19‐fold Cmax); Y axis is the proarrhythmic metric, which is defined as the area under the curve of the net current during an action potential (qNet, see text and Dutta et al.33). Drugs associated with different TdP risk categories are labeled and color‐coded as high risk (red solid squares), intermediate risk (blue triangles), and low risk (green empty squares) based on the clinical risk categorization in Supplementary Table S1. For quinidine, qNet is reported only for Cmax because simulations for higher concentrations caused early afterdepolarizations. Adapted from Dutta et al.33
Figure 5
Figure 5
Relationship between components of the QT interval and underlying ion channel currents. (a) An illustration of the body‐surface ECG and a corresponding ventricular action potential. The QT interval can be divided into depolarization (QRS), early repolarization (J‐Tpeak), and late repolarization (Tpeak‐Tend). Arrows pointing into the action potential are inward currents (sodium and calcium) and arrows pointing out denote outward currents (hERG). The J‐Tpeak interval corresponds with the plateau of the action potential and the balance of inward vs. outward ionic currents. (b) Exposure–response models showing the effects of a predominant hERG blocker (dofetilide; top panel) vs. a balanced hERG and late sodium blocker (ranolazine; bottom panel). Both drugs prolong QTc and Tpeak‐Tend; however, only dofetilide prolongs J‐Tpeakc. The absence of J‐Tpeakc prolongation is a sign of balanced ion channel block between outward (hERG) and inward (late sodium) currents. Adapted from Johannesen et al.41
Figure 6
Figure 6
ECG effects of hERG block alone vs. combined hERG and late sodium block. Results from a clinical trial studying the effects of a hERG blocker alone (dofetilide) and a hERG blocker (dofetilide) in combination with a late sodium blocker (lidocaine or mexiletine). As in Figure5b, dofetilide alone prolongs QTc (left panel), J‐Tpeakc (middle panel), and Tpeak‐Tend (right panel). When lidocaine or mexiletine are coadministered with dofetilide, QTc shortens. Timepoints when lidocaine or mexiletine were coadministered are shown as blue and red, respectively, oriented on the x‐axis according to the dofetilide concentration. The QTc shortening effect of lidocaine and mexiletine (left panel) was entirely due to shortening the J‐Tpeakc interval (middle panel), with no effect on Tpeak‐Tend (right panel). Thus, the combination of late sodium current‐blocking drugs (lidocaine or mexiletine) with a hERG‐blocking drug (dofetilide) recreated the ECG “signature” of ranolazine as shown in Figure5b. Adapted from Johannesen et al.22
Figure 7
Figure 7
Ion channel profiles of drugs in Parts 1 and 2. Ion channel current effects for drugs in Part 1 (chloroquine, ranolazine, verapamil, lopinavir, and ritonavir) and Part 2 (dofetilide and diltiazem) of the clinical study. Each panel shows relative drug‐induced current block from patch clamp experiments; the error bars represent mean±SE of percentage current block measured in the experiments. Vertical lines represent clinical Cmax (solid line) from previous studies and 3‐fold Cmax (dashed line). Ion channel data from Crumb et al.19

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