Evaluation of the J-Tpeak and Tpeak-to-tend intervals of the ECG as proarrhythmia biomarkers in telemetered dogs

Since their implementation, the ICH S7B and E14 guidelines have been successful in that no new approved drugs have been withdrawn from the market due to unanticipated risk of Torsade de Pointe (TdP). While hERG block and QTc prolongation biomarkers are indeed sensitive, they are not specific as multiple drugs block hERG and/or prolong QTc but do not cause TdP. The J-Tpeak interval (JTp) of the ECG has recently been proposed as a novel clinical biomarker to differentiate selective hERG blockers from multi cardiac ion channels inhibitors. Therefore, the present study aimed at evaluating the effects of dofetilide (pure hERG blocker) and dolasetron (balanced ion-channel blocking drug) on QT, JTp and Tpeak-to-Tend (TpTe) Intervals in telemetered conscious dogs, in comparison with levocetirizine, used as a QT negative control drug. The experiments were carried out using 7 dogs previously instrumented with a telemetry implant. Using a cross-over design, each drug was administered at two doses (0.03/0.15, 6/20, 2/10 mg/kg p.o. for dofetilide, dolasetron and levocetirizine, respectively) and ECG monitored over 24 h post-dosing. Dedicated PK sessions were performed to measure corresponding plasma exposure. QT, JTp and TpTe intervals were individually corrected (c) for heart rate variations. Total plasma drug concentrations increased dose-proportionally. Compared to vehicle, dofetilide induced dose-dependent, marked, and long-lasting increases in both QTc and JTpc intervals, confirming predominant hERG blockage by dofetilide. However, no effect was observed on TpTec interval. In contrast, QTc prolongation associated with dolasetron was moderate and transient and no effect on JTpc was observed; interestingly, dolasetron slightly increased TpTec and QRS intervals, as well as PR interval, reflecting its inhibitory effect on calcium and sodium currents. As expected, levocetirizine had no effect, at any dose or timepoint post-dosing. To summarize, pure hERG-blocking drug (such as dofetilide) prolonged both QTc and JTpc, whereas drug with mixed ion channel blockage (such as dolasetron) prolonged QTc but not JTpc. In conclusion, evaluating the effects of a drug on the J-Tpeak interval may be relevant in cardiovascular safety pharmacology studies to complement the QT interval as a sensitive and more specific biomarker for proarrhythmic risk.