Pharmacokinetic and Pharmacodynamic Characterization of Non-antiarrhythmic QT-Prolonging Drugs Associated with Torsades de Pointes

Abstract

QT-prolonging drugs are occasionally associated with Torsades de Pointes (TdP). In this study, we compared the pharmacokinetic and pharmacodynamic characteristics of QT-prolonging drugs associated with TdP and those not associated with TdP. The characteristics included the enzyme responsible for QT-prolonging drug metabolism; the change in drug exposure resulting from enzyme inhibition; the elimination half-life; the volume of distribution, bioavailability and protein binding; the increase in QT interval caused by the drug; and the increase in QT interval in the presence of metabolic inhibition. The results demonstrated that 9 of the 20 selected drugs were metabolized through CYP 3A4 alone and, among them, 4 were torsadogens. In the presence of metabolic inhibition, the increases in maximum plasma concentration (Cmax) of torsadogens were not greater those of nontorsadogens. The increases in AUC, elimination half-lives, volumes of distribution, bioavailability, and protein binding were comparable between the two groups. Almost all torsadogens caused an increase in QT interval greater than 10 msec. In contrast, only one nontorsadogen did. With concomitant administration of enzyme inhibitors, torsadogens caused an increase in QT interval ranging between 30 msec and 82 msec, while those of nontorsadogens were up to a maximum of 16 msec. In conclusion, drugs metabolized through CYP 3A4 alone are not necessarily more likely to be proarrhythmic. The increases in QT interval induced by the torsadogens are slightly greater than those of nontorsadogens. With metabolic inhibition, they are associated with significantly greater increases in QT interval.