Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review

Abstract

Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3-4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug-drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.

Fig. 1

Chemical structure of apixaban

Fig. 2

Absorption, distribution, metabolism, and elimination of apixaban [, , –19]. *Data from subjects following oral administration without bile collection. CYP cytochrome P450, V_ss volume of distribution at steady state

Fig. 3

Mean (+ standard deviation) plasma apixaban concentration vs. time profiles on days 1 and 7 [21]. Reproduced with permission from Frost et al. Br J Clin Pharmacol. 2013;76:776–86

Fig. 4

Effect of intrinsic factors on the pharmacokinetics of apixaban [4]. *Subjects with end-stage renal disease (ESRD) treated with intermittent hemodialysis; reported pharmacokinetic (PK) findings are following a single dose of apixaban post-hemodialysis. ^†Creatinine clearance (CrCl) > 80 mL/min. ^‡Severe, moderate, mild, and normal reflect CrCl of 15 mL/min, 40 mL/min, 65 mL/min, and 100 mL/min based on regression analyses. AUC area under the plasma concentration–time curve, CI confidence interval, C_max maximum plasma concentration. Reproduced with permission from Eliquis (apixaban) US prescribing information

Fig. 5

Effect of co-administered drugs on the pharmacokinetics of apixaban [4]. AUC area under the plasma concentration–time curve from time zero extrapolated to infinity, CI confidence interval, C_max maximum plasma concentration, CYP3A4 cytochrome P450 3A4, P-gp P-glycoprotein, PK pharmacokinetics. Reproduced with permission from Eliquis (apixaban) US prescribing information

Fig. 6

Scatter plots of a international normalized ratio (INR), b activated partial thromboplastin time (aPTT), c modified prothrombin time (mPT), and d, e anti-Xa activity vs. apixaban plasma concentration [35]. Reproduced with permission from Yamahira et al. Int J Clin Pharmacol Ther. 2014;52:564–73