Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects

Abstract Macitentan is an orally active dual endothelin receptor antagonist, which demonstrated a reduction of the risk of morbidity/mortality events in pulmonary arterial hypertension patients. This double-blind, randomized, placebo- and positive-controlled, four-way crossover thorough QTc study was designed to investigate the effects of therapeutic and supratherapeutic doses of macitentan on cardiac repolarization in healthy male and female subjects. Each subject received the following treatments: moxifloxacin 400 mg, macitentan 10 mg, macitentan 30 mg, and placebo. Each treatment period lasted 9 days and was followed by at least 10 days of washout. The primary endpoint of this study was the baseline-adjusted, placebo-corrected QT interval corrected using the Fridericia method (ΔΔQTcF). Pharmacokinetic (PK), safety, and tolerability assessments were performed during each treatment. A total of 64 subjects were randomized. The upper bound of the 2-sided 90% confidence interval for ΔΔQTcF following macitentan was In summary, repeated doses of macitentan 10 mg and 30 mg did not indicate any pro-arrhythmic potential.