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Pharmacokinetic Interaction Between Tadalafil and Bosentan in Healthy Male Subjects
Author(s) -
Wrishko Rebecca E.,
Dingemanse Jasper,
Yu Albert,
Darstein Christelle,
Phillips Diane L.,
Mitchell Malcolm I.
Publication year - 2008
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270008315315
Subject(s) - bosentan , tadalafil , pharmacokinetics , medicine , pharmacology , crossover study , endothelin receptor antagonist , drug interaction , cgmp specific phosphodiesterase type 5 , erectile dysfunction , endothelin receptor , anesthesia , receptor , placebo , alternative medicine , pathology
Tadalafil, an oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a treatment for pulmonary arterial hypertension. Bosentan is an oral endothelin receptor antagonist widely used in the treatment of pulmonary arterial hypertension. Tadalafil is mainly metabolized by cytochrome P450 (CYP) 3A4, and as bosentan induces CYP2C9 and CYP3A4, a pharmacokinetic interaction is possible between these agents. This open‐label, randomized study investigated whether any pharmacokinetic interaction exists between tadalafil and bosentan. Healthy adult men (n = 15; 19–52 years of age) received 10 consecutive days of tadalafil 40 mg once daily, bosentan 125 mg twice daily, and a combination of both in a 3‐period, crossover design. Following 10 days of multiple‐dose coadministration of bosentan and tadalafil, compared with tadalafil alone, tadalafil geometric mean ratios (90% confidence interval [CI]) for AUC τ and C max were 0.59 (0.55, 0.62) and 0.73 (0.68, 0.79), respectively, with no observed change in t max . Following coadministration of bosentan with tadalafil, bosentan ratios (90% CI) for AUC τ and C max were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively. Tadalafil alone and combined with bosentan was generally well tolerated. In conclusion, after 10 days of coadministration, bosentan decreased tadalafil exposure by 41.5% with minimal and clinically irrelevant differences (<20%) in bosentan exposure.