Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes

Project: Research

Investigators

  • James E Tisdale (PI)

Description

Torsades de pointes (TdP) is a potentially fatal ventricular arrhythmia associated with corrected QT (QTc) interval prolongation. More than 50 commonly used drugs available on the US market may cause QTc interval prolongation and TdP. While TdP occurs more commonly in women, 33-45% of all cases of TdP have occurred in men. Older age is a risk factor for drug-induced TdP in men, possibly due to declining serum testosterone concentrations. Available evidence shows an inverse relationship between QTc intervals and serum testosterone concentrations. In addition, experimental data, including those from our laboratory, suggest that both exogenous testosterone or progesterone administration may be protective against prolongation of ventricular repolarization and TdP. Specific Aim 1: Establish the influence of transdermal testosterone administration and oral progesterone administration as preventive methods by which to diminish the degree of drug-induced QT interval prolongation in men 65 years of age or older. Hypothesis: Transdermal testosterone administration and oral progesterone administration both effectively attenuate drug-induced QT interval response in older men. To test this hypothesis, transdermal testosterone, oral progesterone or placebo will be administered in a 3-way crossover study to men 65 years of age or older. QTc interval response to low-dose ibutilide will be assessed. The primary endpoints will be individually-corrected QT interval (QTcI) response to ibutilide, in the presence and absence of testosterone, and in the presence or absence of progesterone: 1) Effect on pre-ibutilide QTcI, 2) Effect on maximum post-ibutilide QTcI, 3) Effect on % change in post-ibutilide QTcI, and 2) Area under the QTcI interval-time curves. Specific Aim 2: Establish the influence of exogenous testosterone as a preventive method by which to reduce the risk of TdP. Hypothesis: Exogenous testosterone reduces the risk of TdP and prolongation of action potential duration (APD) and triangulation. The effect of dihydrotestosterone (DHT) on the incidence of TdP, APD and triangulation will be assessed in an isolated perfused heart model of dofetilide-induced TdP. At the conclusion of this study, we will have established that transdermal testosterone and oral progesterone administration are effective methods of attenuating drug-induced QT interval prolongation. In addition, we will have established that exogenous DHT administration reduces the risk of drug-induced TdP
Award amount$143,000.00
Award date07/01/2015
Program typeGrant-in-Aid
Award ID15GRNT24470168
Effective start/end date07/01/201506/30/2017
StatusFinished