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Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor X a inhibitor, in healthy subjects
Author(s) -
Frost Charles,
Nepal Sunil,
Wang Jessie,
Schuster Alan,
Byon Wonkyung,
Boyd Rebecca A.,
Yu Zhigang,
Shenker Andrew,
Barrett Yu Chen,
MosquedaGarcia Rogelio,
LaCreta Frank
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12106
Subject(s) - apixaban , medicine , pharmacodynamics , pharmacokinetics , partial thromboplastin time , placebo , prothrombin time , anesthesia , adverse effect , rivaroxaban , atrial fibrillation , pharmacology , warfarin , coagulation , alternative medicine , pathology
Aim Apixaban is an oral factor X a 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.