A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium

Abstract

Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. Methods: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). Results: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. Discussion: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.

Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs

“…As previously demonstrated, JTp and Tpe intervals both require HR correction similar to the QT interval. 3 Long RR can lead to overcorrection and short RR can lead to under correction when using the Bazett correction formula. 35,36 The Spence correction formula 17 was shown to efficiently model the QT, JTp, or Tpe interval to HR relationship enabling an individual linear correction similar to the formula created by Holzgrefe et al 37 A high vagal tone or a low sympathetic tone results in a longer QT interval, indicating that both the sympathetic and parasympathetic tones influence the QT interval.…”

“…Similarly, studies by the Health and Environmental Sciences Institute consortium have indicated that the JTp interval is also a suitable alternative to QTc in canines and nonhuman primates. 2,3 Acute stress, mediated (at least, partially) by blood epinephrine, is a common confounding factor known to affect ECG parameters in all species. In a large proportion of humans, epinephrine has been shown to prolong the QT interval.…”

“…Finally, proarrhythmic drugs have been associated with an increase in QT interval as well as JTp interval in human beings and preclinical animal models, such as Beagle dogs. 3,11 The study goal was to compare and evaluate the effects of common ECG confounding factors (ie, body temperature and catecholamine levels) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals, using continuous ECG monitoring in telemetry implanted Beagle dogs. Spatial magnitude (sM) was assessed following administration of verapamil (calcium blocker), dofetilide (I Kr blocker), and ranolazine (late sodium channel blocker) using a 3 derivation ECG and monitoring the QT, JTp, and T-peak to T-end (Tpe) intervals.…”

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation

“…9 Similarly, a recent retrospective analysis of data from nonclinical studies in dogs and nonhuman primates suggests a similar discrimination for JTp nonclinically. 40 Despite this apparent concordance, only a small proportion of responders (34%) support the use of JTp as a novel proarrhythmia biomarker in CV SP studies. It should be noted that a comparable proportion (33%) were undecided regarding support for the use of JTp in SP studies.…”

Considerations in the extrapolation of drug toxicity between humans and dogs

“…However, the ion channel responsible for that change appears to differ in humans vs dogs. This conclusion was reached upon examining the ECG changes associated with the administration of several compounds known to induce ion channel inhibition and ECG changes in humans [6], including dofetilide, sotalol, verapamil, and cisapride.…”