BACKGROUND AND OBJECTIVES: Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects. METHODS: This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed. RESULTS:Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without macitentan. CONCLUSIONS: The absence of effect of macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.
RCT Entities:
BACKGROUND AND OBJECTIVES:Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects. METHODS: This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed. RESULTS: Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without macitentan. CONCLUSIONS: The absence of effect of macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.
Authors: Giuseppe Lippi; Martina Montagnana; Gian Luca Salvagno; Giovanni Poli; Massimo Franchini; Gian Cesare Guidi Journal: Blood Coagul Fibrinolysis Date: 2006-04 Impact factor: 1.276
Authors: Andrea Huppertz; Lars Werntz; Andreas D Meid; Kathrin I Foerster; Jürgen Burhenne; David Czock; Gerd Mikus; Walter E Haefeli Journal: Br J Clin Pharmacol Date: 2018-10-11 Impact factor: 4.335
Authors: N Sommer; M Hecker; K Tello; M Richter; C Liebetrau; M A Weigand; W Seeger; A Ghofrani; H Gall Journal: Anaesthesist Date: 2016-08 Impact factor: 1.041
Authors: Patricia N Sidharta; Paul L M van Giersbergen; Michael Wolzt; Jasper Dingemanse Journal: Br J Clin Pharmacol Date: 2014-11 Impact factor: 4.335