Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 76; no. 5; pp. 776 - 786
• Main Authors: Frost, Charles, Nepal, Sunil, Wang, Jessie, Schuster, Alan, Byon, Wonkyung, Boyd, Rebecca A., Yu, Zhigang, Shenker, Andrew, Barrett, Yu Chen, Mosqueda‐Garcia, Rogelio, LaCreta, Frank
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.11.2013
• Subjects: Administration, Oral; Adult; anticoagulant/thrombolytic drugs; apixaban; cardiovascular pharmacology; coagulation/fibrinolysis; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Humans; International Normalized Ratio; Male; Partial Thromboplastin Time; Pharmacokinetic Dynamic Relationships; pharmacokinetics; Prothrombin Time; Pyrazoles - administration & dosage; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyridones - administration & dosage; Pyridones - pharmacokinetics; Pyridones - pharmacology; Young Adult; anticoagulant/thrombolytic drugs; coagulation/fibrinolysis; pharmacokinetics; cardiovascular pharmacology; apixaban
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12106

Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double‐blind, randomized, placebo‐controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty‐eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post‐dose. Exposure increased approximately in proportion to dose. Apixaban steady‐state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose‐related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10‐fold dose range, with pharmacokinetics with low variability and concentration‐related increases in clotting time measures.