Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

Female sex is an independent risk factor for the potentially fatal drug-induced arrhythmia
(irregular heartbeat) known as torsades de pointes (TdP), which is associated with
prolongation of the corrected QT (QTc) interval on the electrocardiogram (ECG). Mechanisms
for this increased risk in women are not well-understood. QTc interval duration has been
shown to fluctuate throughout the phases of the menstrual cycle. Evidence indicates that the
QTc interval response to drugs that may cause TdP is greater during the menses and ovulation
phases of the menstrual cycle, during which serum progesterone concentrations are lowest,
and lesser during the luteal phase, during which serum progesterone concentrations are
highest. Additional evidence from our laboratory suggests that progesterone may be
protective against TdP. Specific Aim 1: Establish the influence of oral progesterone
administration as a preventive method by which to diminish the degree of drug-induced QT
interval prolongation in women. Working hypothesis: Oral progesterone administration
effectively attenuates enhanced drug-induced QT interval response in women. To test this
hypothesis, progesterone or placebo will be administered in a crossover fashion to women
during the menses phase of the menstrual cycle. QTc interval response to low-dose ibutilide,
a drug known to lengthen the QT interval, will be assessed. The primary endpoint will be
individually-corrected QT interval (QTcI) response to ibutilide, in the presence and absence
of progesterone, which will be assessed by: 1) Effect on maximum change in QTcI, and 2) Area
under the QTcI interval-time curves (AUEC). At the conclusion of this study, we will have
established that oral progesterone administration is a safe and effective method of
attenuating drug-induced QT interval prolongation.