Apixan Mechanism of Action

Pharmacology: Pharmacodynamics: Apixaban, an anticoagulant, is a direct selective and reversible inhibitor of free and clot-bound Factor Xa (FXa). FXa as part of prothrombinase complex consisting also of Factor Va, calcium ions and phospholipid catalyzes the conversion of prothrombin to thrombin. Thrombin activates platelets and catalyzes the conversion of fibrinogen to fibrin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development, it does not require a cofactor (antithrombin III) for its antithrombotic activity.
Apixaban prolongs clotting tests such as prothrombin time (PT), International Normalized Ratio (INR), and activated partial thromboplastin time (aPTT) in a concentration-dependent manner.
Pharmacokinetics: Apixaban demonstrates linear, dose-proportional pharmacokinetics for oral doses up to 10 mg.
Absorption: The absolute bioavailability of apixaban is approximately 50%.
Peak plasma concentrations of apixaban appear approximately 3 to 4 hours after oral administration. Following administration of a single, crushed 5 mg apixaban tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube, its bioavailability was similar to that of a whole tablet taken orally. Absorption of apixaban occurs throughout gastrointestinal tract, about 55% of the drug is absorbed in the distal small intestine and ascending colon. Food does not affect the pharmacokinetics (bioavailability and peak plasma concentrations) or pharmacodynamics of apixaban.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism: Apixaban is metabolized mainly in the liver via CYP3A4/5 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 to inactive metabolites. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is a substrate of transport proteins; p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). No active circulating metabolites have been identified.
Excretion: Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces. An apparent half-life is approximately 12 hours (8-15 hours) following oral administration. Apixaban has a total clearance of approximately 3.3 L/hour.