1. The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers.
- Author
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Walker G, Mandagere A, Dufton C, and Venitz J
- Subjects
- Adolescent, Adult, Anticoagulants pharmacokinetics, Anticoagulants pharmacology, Antihypertensive Agents administration & dosage, Antihypertensive Agents pharmacokinetics, Antihypertensive Agents pharmacology, Area Under Curve, Cross-Over Studies, Drug Interactions, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Phenylpropionates administration & dosage, Phenylpropionates blood, Phenylpropionates pharmacology, Pyridazines administration & dosage, Pyridazines blood, Pyridazines pharmacology, Warfarin administration & dosage, Warfarin blood, Warfarin pharmacology, Young Adult, Anticoagulants blood, Hypertension drug therapy, Phenylpropionates pharmacokinetics, Pyridazines pharmacokinetics, Warfarin pharmacokinetics
- Abstract
Aims: Ambrisentan is an oral, propanoic acid-based endothelin receptor antagonist often co-administered with warfarin to patients with pulmonary arterial hypertension. The aim of this study was to evaluate the potential for ambrisentan to affect warfarin pharmacokinetics and pharmacodynamics., Methods: In this open-label cross-over study, 22 healthy subjects received a single dose of racemic warfarin 25 mg alone and after 8 days of ambrisentan 10 mg once daily. Assessments included exposure (AUC(0-last)) and maximum plasma concentration (C(max)) for R- and S-warfarin, and International Normalized Ratio maximum observed value (INR(max)) and area under the curve (INR(AUC(0-last))). The effects of warfarin on ambrisentan steady-state pharmacokinetics and the safety of ambrisentan/warfarin co-administration were assessed. Data are presented as geometric mean ratios., Results: Ambrisentan had no significant effects on the AUC(0-last) of R-warfarin [104.7; 90% confidence interval (CI) 101.7, 107.7) or S-warfarin (101.6; 90% CI 98.4, 105.0). Similarly, ambrisentan had no significant effects on the C(max) of R-warfarin (91.6; 90% CI 86.2, 97.4) or S-warfarin (89.9; 90% CI 84.8, 95.3). Consistent with these observations, little pharmacodynamic change was observed for INR(max) (85.3; 90% CI 82.4, 88.2) or INR(AUC(0-last)) (93.0; 90% CI 90.8, 95.3). In addition, co-administration of warfarin did not alter ambrisentan steady-state pharmacokinetics. Adverse events were infrequent, and there were no bleeding adverse events., Conclusions: Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin. Therefore, significant dose adjustments of either drug are unlikely to be required with co-administration.
- Published
- 2009
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