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This Article Full Text Full Text (PDF) All Versions of this Article: 0091270008315315v1 48/5/610    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Google Scholar Articles by Wrishko, R. E. Articles by Mitchell, M. I. PubMed PubMed Citation Articles by Wrishko, R. E. Articles by Mitchell, M. I.

Pharmacokinetic Interaction Between Tadalafil and Bosentan in Healthy Male Subjects

From Lilly Research Laboratories, Indianapolis, Indiana (Dr Wrishko, Ms Darstein, Dr Phillips); Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (Dr Dingemanse); ICOS Corporation, Bothell, Washington (Dr Yu); and Lilly Research Centre, Windlesham, Surrey, UK (Mr Mitchell).

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 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 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.

Key Words: Tadalafil • bosentan • pharmacokinetic interaction • pulmonary arterial hypertension

Address for correspondence: Rebecca E. Wrishko, PhD, Lilly Research Laboratories, Lilly Corporate Center, DC 0730, Indianapolis, IN 46285; e-mail: wrishkore{at}lilly.com.