How Rivaroxaban Works
Rivaroxaban is a selective and competitive active site-directed, reversible factor Xa inhibitor that directly inhibits both free factor Xa and prothrombinase complex-bound factor Xa, thereby decreasing thrombin generation and preventing clot formation. 1
Mechanism of Action
- Rivaroxaban selectively inhibits factor Xa with 10,000-fold greater selectivity than for other trypsin-like serine proteases 2
- It acts through electrostatic interaction with Asp189 in the S1 pocket of factor Xa, specifically involving the chlorine substituent of the chlorothiophene moiety interacting with Tyr228 2
- As a small molecule (molecular weight 436 g/mol), rivaroxaban can inhibit:
- By inhibiting factor Xa, rivaroxaban prevents the conversion of prothrombin to thrombin, thereby reducing thrombin generation and subsequent clot formation 1
Pharmacokinetic Properties
- Rivaroxaban has high oral bioavailability (80-100%) for the 10 mg dose, which is not affected by food 4
- For 15 mg and 20 mg doses, food increases bioavailability (AUC and Cmax increasing by 39% and 76% respectively) 1
- Peak plasma concentration occurs at 2-4 hours after tablet intake 1, 4
- The half-life ranges from 7-11 hours in young subjects and 11-13 hours in elderly subjects 4
- Rivaroxaban is highly protein-bound (92-95%), primarily to albumin 2
- Elimination occurs through dual pathways:
- Approximately 66% via kidneys (36% as unchanged drug)
- Approximately 28% via feces (7% as unchanged drug) 2
Metabolism and Drug Interactions
- Rivaroxaban is metabolized via oxidative and hydrolytic pathways 2
- CYP3A4 and CYP2J2 are the primary enzymes responsible for oxidative metabolism 2
- As a substrate of CYP3A4 and P-glycoprotein, rivaroxaban is not recommended for concomitant use with strong inhibitors of both pathways (e.g., azole antimycotics, protease inhibitors) 4
- Drugs that alter gastric pH (H2-receptor antagonists, antacids, PPIs) do not significantly affect rivaroxaban's bioavailability 1
Pharmacodynamic Effects
- Rivaroxaban produces dose-dependent inhibition of factor Xa activity 1
- It prolongs prothrombin time (PT), activated partial thromboplastin time (aPTT), and heparin clotting time 2
- Maximum inhibition of factor Xa activity occurs between 1-4 hours after administration 2
- Unlike traditional anticoagulants, rivaroxaban does not affect bleeding time or platelet aggregation when used alone 2
- The inhibitory effect on factor Xa is concentration-dependent with an inhibitory constant (Ki) of 0.4 nmol/L 3
Clinical Implications and Monitoring
- Rivaroxaban's predictable pharmacokinetic and pharmacodynamic profile allows for fixed dosing regimens without routine coagulation monitoring 4, 5
- Dose adjustments are required in patients with moderate renal impairment (CrCl 15-49 mL/min) 6
- In cases of overdose or emergency situations:
Dosing Considerations
- For VTE prevention after orthopedic surgery, 10 mg once daily is typically used 2
- For VTE treatment and stroke prevention in atrial fibrillation, 20 mg once daily (or 15 mg once daily in moderate renal impairment) is recommended 6
- Rivaroxaban 15 mg and 20 mg tablets should be taken with food to optimize bioavailability 1
Common Pitfalls and Caveats
- Unlike warfarin, rivaroxaban has no specific antidote, making management of life-threatening bleeding challenging 2
- The INR is not suitable for monitoring rivaroxaban activity as different thromboplastins have varying sensitivities to factor Xa inhibitors 2
- Concomitant use with NSAIDs or antiplatelet agents may significantly increase bleeding risk 2
- Regular assessment of renal function is recommended, especially in patients with moderate renal impairment 6