Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects

Abstract

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

Keywords: P-glycoprotein; amiodarone; digoxin; drug-drug interaction; omecamtiv mecarbil.