Abstract
Drug-induced human ether-à-go-go-related gene (hERG) channel block and QT interval prolongation increase torsade de pointes (TdP) risk. However, some drugs block hERG channels and prolong QT interval with low TdP risk, likely because they block additional inward currents. We investigated the utility of J-Tpeak interval, a novel biomarker of inward current block and TdP risk, in conscious telemetered guinea pigs. Electrocardiogram parameters were analysed in Hartley guinea pigs orally administered one of eight test compounds (dofetilide, flecainide, nifedipine, quinidine, quinine, ranolazine, sotalol, verapamil) or vehicle alone as controls. Heart rate-corrected QT (QTcX) and J-Tpeak (J-TpeakcX) were calculated to evaluate the relations of QT–RR and J-Tpeak–RR. Dofetilide and sotalol significantly increased ΔQTcX and ΔJ-TpeakcX intervals to similar degrees. Quinidine, quinine and flecainide also increased ΔQTcX and ΔJ-TpeakcX intervals, but the degrees of ΔJ-TpeakcX interval prolongation were shorter than those of ΔQTcX interval prolongation. Ranolazine showed slight increasing trends in ΔQTcX and ΔJ-TpeakcX intervals, but the differences were not significant. Verapamil and nifedipine did not increase the ΔQTcX or ΔJ-TpeakcX intervals. Based on the relations of ΔΔJ-TpeakcX and ΔΔQTcX intervals, dofetilide, sotalol and quinidine were classified as high risk for TdP, quinine, flecainide and ranolazine were classified as intermediate risk and verapamil and nifedipine were classified as low risk. These results supported the usefulness of J-Tpeak interval assessment in conscious guinea pigs for predicting drug-induced balanced block of inward currents and TdP risk in early-stage preclinical studies.
Published Version
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