The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

WHAT IS ALRADY KNOWN ABOUT THIS SUBJECT • Warfarin anticoagulation therapy is commonly administered to patients with pulmonary arterial hypertension (PAH) to reduce the risk of thrombosis and embolism. • Ambrisentan is an orally active, propanoic acid‐based endothelin receptor antagonist that is likely to be co‐administered with warfarin to PAH patients. • Concomitant therapies that induce or inhibit warfarin metabolism may alter the systemic exposure of warfarin and significantly alter clotting time, as measured by prothrombin time and International Normalized Ratio, thereby requiring substantial adjustments to warfarin dose. WHAT THIS STUDY ADDS • This study was undertaken in healthy subjects to identify any potential drug interactions between ambrisentan and warfarin. • Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics or pharmacodynamics of warfarin; conversely, a single dose of warfarin had no clinically relevant effects on the steady‐state pharmacokinetics of ambrisentan. • Therefore, co‐administration of ambrisentan with warfarin should not require adjustment of the therapeutically effective dosing regimen for either drug. 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 (AUC0–last) and maximum plasma concentration (Cmax) for R‐ and S‐warfarin, and International Normalized Ratio maximum observed value (INRmax) and area under the curve (INRAUC(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 AUC0–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 Cmax 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 INRmax (85.3; 90% CI 82.4, 88.2) or INRAUC(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.