Once-daily macitentan 75 mg had no clinically relevant pharmacokinetic effects on sildenafil, riociguat, or rosuvastatin, indicating no dose adjustments are needed for co-administration.
Does co-administration of macitentan 75 mg alter the pharmacokinetics of sildenafil, riociguat, or rosuvastatin in healthy male adults?
Co-administration of high-dose macitentan (75 mg) with sildenafil, riociguat, or rosuvastatin does not cause clinically relevant pharmacokinetic interactions, indicating no dose adjustments are necessary.
Absolute Event Rate: 0% vs 0%
Macitentan is an oral, dual ETA/ETB endothelin receptor antagonist, currently approved in adults for the treatment of pulmonary arterial hypertension (PAH) at a once-daily dose of 10 mg. Pre-clinical and clinical data suggest that greater ETB receptor inhibition may result in greater efficacy. This hypothesis is being tested in the Phase 3 UNISUS study (NCT04273945), comparing once-daily macitentan 75 mg versus macitentan 10 mg. The present Phase 1 study (NCT04211272) evaluated the pharmacokinetics and safety of concomitant administration of once-daily macitentan 75 mg at steady state with substrates of either breast cancer resistance protein (BCRP) transporter (e.g., riociguat and rosuvastatin) or cytochrome P450 3A4 (CYP3A4) enzymes (e.g., sildenafil and tadalafil) in healthy male adults. Macitentan was administered once daily at 10 mg on Days 1 and 2, 37.5 mg on Days 3-5, and 75 mg on Days 6-13. Participants received a single oral dose of sildenafil (20 mg) on Days -4 and 13, riociguat (1 mg) on Days -3 and 10, or rosuvastatin (10 mg) on Days -4 and 10. Geometric mean ratios for the maximum concentration and area under the curve of the substrate and 90% confidence intervals showed no clinically relevant effects on exposure for sildenafil, riociguat, or rosuvastatin when administered alone or with macitentan 75 mg. Co-administration of macitentan and the substrates was generally well tolerated. Due to the lack of clinically relevant drug-drug pharmacokinetic interactions, no dose adjustment is deemed necessary when co-administering once-daily macitentan 75 mg with BCRP or CYP3A4 substrates.
Csonka et al. (Wed,) reported a other. Once-daily macitentan 75 mg had no clinically relevant pharmacokinetic effects on sildenafil, riociguat, or rosuvastatin, indicating no dose adjustments are needed for co-administration.