Apixaban Pharmacokinetics and Pharmacodynamics in Subjects with Mild or Moderate Hepatic Impairment.

Abstract

BackgroundHepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.ObjectiveThis study evaluated the effect of mild or moderate (Child–Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.MethodsThis open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects. Subjects received a single oral apixaban 5-mg dose (day 1). Pharmacokinetic, pharmacodynamic, and safety assessments were completed at prespecified time points. Apixaban maximum plasma concentration and area under the concentration–time curve to infinity were compared between subjects with hepatic impairment and healthy subjects.ResultsApixaban area under the concentration–time curve to infinity point estimates and 90% confidence intervals were 1.03 (0.80–1.32) and 1.09 (0.85–1.41) for subjects with mild and moderate hepatic impairment vs healthy subjects. Maximum plasma concentration results were similar. Mean (standard deviation) apixaban unbound fraction was 6.8% (1.4), 7.9% (1.8), and 7.1% (1.3) in subjects with mild or moderate hepatic impairment and in healthy subjects. Mean change from baseline in international normalized ratio (3 h post-dose) was 14.7%, 12.7%, and 10.7% for subjects with mild or moderate hepatic impairment and healthy subjects, respectively. A direct relationship was observed between apixaban anti-factor Xa activity and plasma concentration across groups. No serious adverse events or discontinuations due to adverse events occurred.ConclusionsMild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.