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 <10 ms at all time points and no correlation was observed between ΔΔQTcF and PK parameters. Findings in the analysis of the morphological patterns of the ECGs were randomly distributed across all treatments and did not indicate an association with macitentan. Macitentan was well tolerated in this study. Headache and nasopharyngitis were the most frequently reported adverse events. No effects on clinical laboratory and vital signs parameters were observed. In summary, repeated doses of macitentan 10 mg and 30 mg did not indicate any pro-arrhythmic potential.
Keywords: ICH E14; Moxifloxacin; PAH; QT prolongation; Thorough QT study.
Copyright © 2014 Elsevier Ltd. All rights reserved.