Linear Correlation Supports Common Mechanism of Action for Ranolazine

SAN FRANCISCO, CA—At ACC.13, the American College of Cardiology's 62nd Annual Scientific Session, Ramin Farzaneh-Far, MD, FACC, from Gilead Sciences, Foster City, CA, reported that the QTc interval shortening and anti-ischemic effect of ranolazine provide evidence of a similar mechanism of action, such as inhibition of late sodium current  (INA,L).

The anti-ischemic effects of ranolazine are dose-dependent in patients with coronary artery disease (CAD). Patients with long-QT syndrome 3 (LQT3) experience a dose-dependent shortening of the QTc interval with ranolazine therapy. Dr. Farzaneh-Far and colleagues studied the relationship between QTc shortening in patients with LQT3 and the anti-ischemic effects of ranolazine. The study researchers hypothesized that the pharmacokinetic and pharmacodynamic relationships of ranolazine in CAD and LQT3 were dose-dependent and parallel.

A post-hoc analysis of pharmacodynamics and pharmacokinetic data was performed from two studies. The first was the LQT3 Study, an open-label study of the effect of ranolazine to shorten the QTc interval in patients with LQT3 (n=5). The second was the MARISA study, a randomized, double-blind cross-over study of the effect of ranolazine on exercise-induced ST depression in patients with CAD (n=191).

In the LQT3 Study, patients were given an 8-hour infusion of IV ranolazine (45mg/hr for 3 hours followed by 90mg/hr for 5 hours). Time-matched 12-lead electrocardiograms were obtained for 24 hours prior to, and on the day of infusion. In addition, blood samples for pharmacokinetics were drawn hourly during infusion and then at 2, 4, and 16 hours following completion of infusion.

In the MARISA study, patients were randomized to sustained-release ranolazine 500mg, 1,000mg, 1,500mg or placebo. Each dose was administered twice daily for one week. Exercise testing performed at the end of each treatment period. 

A linear and parallel correlation was observed for ranolazine concentration, change in QTc shortening in LQT3, and time to 1mm ST-segment depression in CAD (R2=0.91, R2=0.88; P<0.05, respectively). Similar correlations were obtained for other anti-ischemic effects of ranolazine such as exercise duration (R2=0.88; P<0.05), time to angina (R2=0.96; P<0.05), and maximum ST depression (R2=0.96; P<0.05).

Dr. Farzaneh-Far stated that the linear and parallel correlation between the QTc interval shortening and the anti-ischemic effects of ranolazine “is consistent with a common underlying mechanism of action, namely inhibition of INa, L.” They further concluded that QTc shortening in patients with LQT3 may be a useful surrogate marker for anti-ischemic dose selection in this drug class.