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Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers
Author(s) -
Spence Rebecca,
Mandagere Arun,
Dufton Christopher,
Venitz Jürgen
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 - 10.1177/0091270008324180
Subject(s) - ambrisentan , sildenafil , pharmacokinetics , pharmacology , medicine , active metabolite , cmax , cgmp specific phosphodiesterase type 5 , bosentan , endothelin receptor , receptor
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.