Reducing the Risk of Drug-Induced ventricular repolarization lengthening

Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation. Female sex and age > 65 years are risk factors for QT prolongation and TdP, possibly due to the effect of sex hormones. Progesterone shortens QT interval, while estrogen lengthens QT interval in females. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. J-Tpeak (JTp) and Tpeak-Tend (Tpe) intervals are biomarkers of early and late repolarization. Population pharmacokinetic/pharmacodynamic (PK/PD) models can be used to describe exposure-response relationships and identify sources of variability. In this study, data were pooled from four clinical trials with similar study design investigating the effect of progesterone on ibutilide-induced ventricular repolarization lengthening in healthy premenopausal women during menses or ovulation phase and healthy postmenopausal women. A nonlinear mixed effect model of ibutilide - QTc interval was first developed with preliminary data from 33 subjects. The model was then updated with new data from a total of 52 subjects, assessing the effect of progesterone on drug-induced QTc interval lengthening and identifying sources of variability through covariate analysis. Finally, two PK/PD models of ibutilide - baseline corrected JTpc (ΔJTpc) interval and Tpe (ΔTpe) interval were developed to assess the effect of progestogen on ibutilide-induced early and late repolarization lengthening. Progesterone showed protective effect against ibutilide-induced QTc interval lengthening, mainly through the shortening of pre-ibutilide baseline QTc interval. Body weight, age, race, hypertension, electrocardiogram (ECG) type and estradiol concentration were not significant covariates. Progesterone attenuates ibutilide-induced lengthening of late ventricular repolarization but did not show significant effect on ibutilide-induced early repolarization lengthening. Higher estradiol concentration was related to higher ibutilide-induced early repolarization lengthening. Black race was related to lower ibutilide-induced late repolarization lengthening.