Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc) interval prolongation, which can be induced by > 150 commonly prescribed drugs. TdP risk is higher in women and is modulated by the ratio of serum progesterone and estradiol; the higher the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa. TdP risk increases with age, likely due to declining postmenopausal progesterone concentrations. Methods to reduce TdP risk in postmenopausal women requiring therapy with QTc interval-prolonging drugs have not been developed. In addition, the differential effects of progesterone on drug-induced lengthening of early vs late ventricular repolarization in humans are unknown. The investigators have previously shown that oral progesterone attenuates QTc interval lengthening in young women during the menses phase when serum estradiol concentrations are low. However, whether oral progesterone remains effective for attenuating drug-induced QTc interval lengthening during menstrual cycle phases with higher serum estradiol concentrations is unknown. The efficacy of oral progesterone for attenuating drug-induced QTc interval lengthening in postmenopausal women is also unknown. Specific Aim1: Determine the efficacy of oral progesterone as a preventive method to diminish drug-induced QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in postmenopausal women. Specific Aim 3: Determine the efficacy of oral progesterone to diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high. Specific Aim 4: Specific Aim 4: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high.

Concurrent prospective, randomized, double-blind, placebo-controlled two-way crossover-design studies will be conducted in a) Postmenopausal women > 50 years of age (n=20) and b) Premenopausal women 21-40 years of age (n=20) who will be studied during the ovulation phase of the menstural cycle. QTc interval response to low-dose ibutilide will be assessed. Subjects will receive, in randomized order (with a minimum two-week washout phase) oral progesterone 400 mg or placebo once daily for 7 days. On the morning after the 7th dose, subjects will present to the Indiana Clinical Research Center to receive one dose of the QT interval-lengthening drug ibutilide 0.003 mg/kg, after which ECGs and blood for determination of serum ibutilide concentrations will be obtained serially for 8 hours. Primary outcome measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected QT intervals, 2) Maximum QTFrid and QTFram intervals following ibutilide, 3) Maximum % change in QTFrid and QTFram intervals following ibutilide, 4) Area under the QTFrid and QTFram interval-time curves from 0-1 and 0-8 hours. Secondary outcome measures: 1) J-Tpeak interval, 2) Tpeak-Tend interval, and 5) Incidence of progesterone and ibutilide adverse effects. These studies will establish oral progesterone as a safe and effective method of attenuating drug-induced QTc interval lengthening in postmenopausal women.