Abstract
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.
Publication types
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Adolescent
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Adult
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Analysis of Variance
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Area Under Curve
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Chromatography, High Pressure Liquid
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Cross-Over Studies
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Drug Interactions
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Endothelin A Receptor Antagonists
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Female
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Follow-Up Studies
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Half-Life
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Headache / chemically induced
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Humans
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Male
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Middle Aged
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Pain / chemically induced
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Phenylpropionates / administration & dosage
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Phenylpropionates / adverse effects
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Phenylpropionates / pharmacokinetics*
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors / administration & dosage
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Phosphodiesterase Inhibitors / adverse effects
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Phosphodiesterase Inhibitors / pharmacokinetics
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Piperazines / administration & dosage
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Piperazines / adverse effects
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Piperazines / blood
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Piperazines / pharmacokinetics*
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Purines / administration & dosage
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Purines / adverse effects
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Purines / blood
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Purines / pharmacokinetics
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Pyridazines / administration & dosage
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Pyridazines / adverse effects
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Pyridazines / pharmacokinetics*
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Sildenafil Citrate
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Sulfones / administration & dosage
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Sulfones / adverse effects
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Sulfones / blood
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Sulfones / pharmacokinetics*
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Tandem Mass Spectrometry
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Young Adult
Substances
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Endothelin A Receptor Antagonists
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Phenylpropionates
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Piperazines
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Purines
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Pyridazines
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Sulfones
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Sildenafil Citrate
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ambrisentan