The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers.
OBJECTIVE
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.
Walker
Gennyne
G
Gilead Sciences Inc., Westminster, CO, USA. gennyne.walker@gilead.com
Mandagere
Arun
A
Dufton
Christopher
C
Venitz
Jürgen
J
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
D000925:Anticoagulants; D000959:Antihypertensive Agents; D010666:Phenylpropionates; D011724:Pyridazines; D014859:Warfarin; C467894:ambrisentan