Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study

Abstract

Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐T peak (J‐T peak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐T peak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT peak ‐T end . Absence of J‐T peak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.

QT Interval Prolongation Under Hydroxychloroquine/Azithromycin Association for Inpatients With SARS‐CoV‐2 Lower Respiratory Tract Infection

“…6 This discrepancy between increased proportion of extreme QT prolongation reported in the recent experiences with HCQ and the relative low number of clinical events, 22 confirms that QT prolongation is a sensitive, but not specific surrogate for TdP risk. 23 This relationship between QT prolongation and TdP is not linear as drugs that prolong the QT have not consistently been associated with cardiac arrythmias ("balanced blockers"). The CiPA initiative demonstrated the importance of the QTc and J-Tpeak prolongation as a robust predictor of the torsadogenic potential in case of a predominant hERG blocker, in contrast with a balanced blocker, i.e.…”

Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives

“…The activities of K + channels are the major determinants of the repolarization of cardiac myocytes. Chloroquine and hydroxychloroquine have been reported to inhibit multiple K + currents, including the inward rectifier K + (Kir) current ( I K1 ) [ 35 – 38 ], the rapidly activating delayed rectifier K + current ( I Kr ) associated with the human eEther-a-go-go-go related gene ( hERG ) [ 39 , 40 ], the fast transient outward K + current ( I to ) [ 41 ], and the ATP-sensitive inward rectifier K + current (K ATP ) [ 42 , 43 ]. I K1 : Chloroquine, hydroxychloroquine and other quinines inhibit the cardiac I K1 current and can induce lethal ventricular arrhythmias.…”

“…However, not all hERG blockers have a high risk of Torsade de Pointes . There are drugs that block hERG and prolong the heart rate-corrected QT (QTc) interval but have a low risk of Torsade de Pointes (e.g., ranolazine, verapamil, and amiodarone) because they block other inward currents such as late Na + and/or L-type Ca 2+ currents [ 39 ]. Blocking these inward currents has antiarrhythmic effects by preventing early afterdepolarizations [ 39 ].…”

The Potential Role of the J‐Tpeak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

“…14 Recent clinical studies, including a retrospective analysis of 34 thorough QT studies and 3 prospective clinical trials including 11 drugs and 5 drug combinations, have provided evidence that the absence of significant J-T peak c prolongation in the presence of QTc prolongation may be a useful "ECG signature" of a balanced ion channel-blocking drug. [15][16][17][18] Drugs that predominantly block the hERG channel prolong QTc by prolonging both J-T peak c and T peak -T end , whereas drugs that block the hERG channel along with calcium and/or late sodium channels prolong QTc by prolonging T peak -T end with limited or no effect on the J-T peak c interval. For example, dofetilide, quinidine, and moxifloxacin (predominant hERG blockers) prolong QTc by prolonging both J-T peak c and T peak -T end , whereas ranolazine (a balanced hERG and late sodium blocker), verapamil (a balanced hERG and L-type calcium blocker), lopinavir/ritonavir (blocker of hERG, L-type calcium, and late sodium), and drug combinations of dofetilide (hERG blocker) with lidocaine or mexiletine (late sodium blockers) prolonged QTc by prolonging T peak -T end but not J-T peak c. As already noted, verapamil and ranolazine have not been shown to cause torsade despite >15 years of use, even though both prolong the QTc interval.…”

“…For example, dofetilide, quinidine, and moxifloxacin (predominant hERG blockers) prolong QTc by prolonging both J-T peak c and T peak -T end , whereas ranolazine (a balanced hERG and late sodium blocker), verapamil (a balanced hERG and L-type calcium blocker), lopinavir/ritonavir (blocker of hERG, L-type calcium, and late sodium), and drug combinations of dofetilide (hERG blocker) with lidocaine or mexiletine (late sodium blockers) prolonged QTc by prolonging T peak -T end but not J-T peak c. As already noted, verapamil and ranolazine have not been shown to cause torsade despite >15 years of use, even though both prolong the QTc interval. 4,18 Thus, conceptually, such an "ECG signature," in conjunction with preclinical ion channel data and in-silico modeling, might have a role in distinguishing mechanistically different profiles that are clinically relevant to safety-related decision making such as torsade risk. As discussed below, this signature might be informative during individual drug development and to assess targeted drug combinations, or both.…”