Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers.
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-infinity)) 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-infinity) 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-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) 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.
Spence
Rebecca
R
Gilead Sciences, Inc, 7575 W. 103rd Ave, Westminster, CO 80021, USA. becky.spence@gilead.com
Mandagere
Arun
A
Dufton
Christopher
C
Venitz
Jürgen
J
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D010666:Phenylpropionates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011724:Pyridazines; D013450:Sulfones; D000068677:Sildenafil Citrate; C467894:ambrisentan