Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 78; no. 5; pp. 1035 - 1042
• Main Authors: Sidharta, Patricia N., Giersbergen, Paul L. M., Wolzt, Michael, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: England BlackWell Publishing Ltd 01.11.2014
• Subjects: Administration, Oral; Adolescent; Adult; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Drug Administration Schedule; Drug Interactions; drug−drug interaction; endothelin receptor antagonist; Endothelin Receptor Antagonists - administration & dosage; Endothelin Receptor Antagonists - blood; Endothelin Receptor Antagonists - pharmacokinetics; Endothelin Receptor Antagonists - pharmacology; healthy subjects; Healthy Volunteers; Humans; macitentan; Male; Metabolic Clearance Rate; Middle Aged; pharmacokinetics; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - blood; Phosphodiesterase 5 Inhibitors - pharmacokinetics; Phosphodiesterase 5 Inhibitors - pharmacology; Piperazines - administration & dosage; Piperazines - blood; Piperazines - pharmacokinetics; Piperazines - pharmacology; Purines - administration & dosage; Purines - blood; Purines - pharmacokinetics; Purines - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; sildenafil; Sildenafil Citrate; Substrate Specificity; Sulfonamides - administration & dosage; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Young Adult; pharmacokinetics; endothelin receptor antagonist; healthy subjects; macitentan; sildenafil; drug−drug interaction
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12447

Aim To study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects. Methods In this open‐label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of macitentan and its active metabolite ACT‐132577 (treatments A and C) and sildenafil and its N‐desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non‐compartmentally. Results The pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT‐132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N‐desmethylsildenafil were not affected by macitentan. All treatments were well tolerated. Conclusion A minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.