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

From Gilead Sciences, Inc, Westminster, Colorado (Dr Spence, Dr Mandagere, Dr Dufton), and Virginia Commonwealth University, Richmond, Virginia (Dr Venitz).

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET_A-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC_0-) and maximum plasma concentration (C_max) 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 AUC_0- and C_max 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 C_max was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC_0- (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C_max was increased slightly (113.4% [99.6%-129.1%]), and AUC_0- 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.

Key Words: Ambrisentan • sildenafil • endothelin receptor antagonist (ERA) • phosphodiesterase type 5 (PDE-5) inhibitor • pharmacokinetics • pulmonary arterial hypertension

Address for reprints: Rebecca Spence, PhD, Gilead Sciences, Inc, 7575 W. 103rd Ave, Westminster, CO 80021; e-mail: becky.spence{at}gilead.com.

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