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

Background: Hepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.

Objective: This study evaluated the effect of mild or moderate (Child-Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.

Methods: This 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.

Results: Apixaban 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.

Conclusions: Mild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.