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First published on October 1, 2008, doi:10.1177/0091270008324180

The Journal of Clinical Pharmacology 2008;48:1451.

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©© 2008 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology, 10.1177/0091270008324180

Article

Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers

Rebecca Spence 1*, Arun Mandagere 1, Christopher Dufton 1, and Jürgen Venitz 2

1 Gilead Sciences, Inc
2 Virginia Commonwealth University

* To whom correspondence should be addressed. E-mail: becky.spence{at}gilead.com.


  Abstract
The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ETA-selective, propanoic acid–based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC0-{infty}) and maximum plasma concentration (Cmax) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC0-{infty} and Cmax for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan Cmax was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC0-{infty} (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil Cmax was increased slightly (113.4% [99.6%-129.1%]), and AUC0-{infty} was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.
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