How does apixaban work?

How Apixaban Works

Mechanism of Action

Apixaban is a selective, direct inhibitor of factor Xa (FXa) that prevents thrombin generation and clot formation by blocking the conversion of prothrombin to thrombin. 1

Primary Anticoagulant Activity

• Apixaban selectively inhibits factor Xa without requiring antithrombin III for its antithrombotic activity, distinguishing it from heparin-based anticoagulants 1
• The drug inhibits both free factor Xa in the circulation and clot-bound factor Xa, as well as factor Xa within the prothrombinase complex 2, 1
• By blocking factor Xa, apixaban prevents the conversion of prothrombin into thrombin, thereby reducing fibrin formation and thrombus development 1

Effects on Platelet Function

• Apixaban has no direct effect on platelet aggregation 1
• However, it indirectly inhibits platelet aggregation by reducing thrombin generation, since thrombin is a potent platelet activator 1, 3
• This indirect mechanism contributes to its overall antithrombotic effect while potentially reducing bleeding risk compared to agents that directly affect platelets 3

Pharmacokinetic Profile

Absorption and Bioavailability

• Apixaban has approximately 50% oral bioavailability for doses up to 10 mg 1
• Peak plasma concentrations occur 3-4 hours after oral administration 2, 1
• Food does not affect bioavailability, allowing flexible dosing with or without meals 1
• At doses ≥25 mg, absorption becomes dissolution-limited with decreased bioavailability 1

Distribution and Protein Binding

• Apixaban is highly bound to plasma proteins (approximately 87%) 2
• The drug has a small volume of distribution, contributing to its predictable pharmacokinetic profile 3

Metabolism and Elimination

• Apixaban is 25% hepatically metabolized, primarily via CYP3A4, with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2 2
• The drug is a substrate for P-glycoprotein (P-gp), a drug efflux transporter in intestinal and renal tubular membranes 2
• Multiple elimination pathways include renal excretion (approximately 27% of total clearance), metabolism, biliary excretion, and direct intestinal excretion 2, 1
• The elimination half-life is approximately 12 hours, allowing for twice-daily dosing 2
• Steady-state concentrations are achieved within 3 days of regular dosing 2

Clinical Pharmacodynamics

Effects on Coagulation Tests

• Apixaban prolongs standard clotting tests including prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT) 1
• However, these changes are small, highly variable, and not useful for monitoring the anticoagulation effect 1
• A concentration-dependent increase in anti-factor Xa activity occurs, but this test is not recommended for routine monitoring 1

Drug Interactions

• Strong dual inhibitors of both CYP3A4 and P-glycoprotein (such as ketoconazole or ritonavir) are contraindicated as they significantly increase apixaban plasma concentrations 2
• Coadministration with enoxaparin or naproxen increases anti-FXa activity by 50-60% 1
• No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel 1

Dose Adjustments Based on Pharmacokinetics

Renal Impairment

• No dose adjustment is required for mild to moderate renal impairment 1
• Anti-FXa activity adjusted for exposure remains similar across renal function categories 1
• Apixaban should be avoided in severe renal impairment (CrCl <15 mL/min) 2, 1

Hepatic Impairment

• No dose adjustment is required for mild hepatic impairment (Child-Pugh class A) 1
• Dosing recommendations cannot be provided for moderate hepatic impairment (Child-Pugh class B) due to intrinsic coagulation abnormalities and limited clinical experience 1
• Apixaban is not recommended in severe hepatic impairment (Child-Pugh class C) 1