Apixaban Single‐Dose Pharmacokinetics, Bioavailability, Renal Clearance, and Pharmacodynamics Following Intravenous and Oral Administration

Abstract This randomized, double‐blind, placebo‐controlled, ascending single intravenous (IV) bolus‐dose study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of apixaban, a direct factor Xa (FXa) inhibitor approved for multiple indications. Eight healthy subjects were randomized 3:1 (apixaban:placebo) within each IV dose cohort (0.5, 1.25, 2.5, 3.75, and 5 mg). The 2.5‐mg IV panel also received 5 mg of oral apixaban or placebo. Blood samples were collected for PK and PD, including international normalized ratio, modified prothrombin time (mPT), and anti‐FXa activity. Apixaban had 66.2% oral bioavailability, dose‐proportional exposure, 17 to 26 L steady‐state volume of distribution, and 3.2 to 3.5 L/h total plasma clearance. Renal clearance was ≈27%. Anti‐FXa activity and mPT changes followed the apixaban plasma concentration–time profile; both were highly correlated with concentration (R 2 = 0.99 and R 2 = 0.93 for anti‐FXa activity and mPT, respectively). International normalized ratio remained within reference range (0.9‐1.3). There were no serious or bleeding‐related adverse events. Overall, an apixaban single IV bolus was safe and well tolerated over a 10‐fold dose range by these subjects. Apixaban had good oral bioavailability, dose‐proportional exposure, and constant plasma clearance over a broad dose range, with modest renal clearance. Apixaban PD were consistent with reversible FXa inhibition.