Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor <scp>X</scp>a inhibitor, in healthy subjects

<jats:sec><jats:title>Aim</jats:title><jats:p>Apixaban is an oral factor <jats:styled-content style="fixed-case">X</jats:styled-content>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.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>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 (<jats:styled-content style="fixed-case">AEs</jats:styled-content>). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (<jats:styled-content style="fixed-case">INR</jats:styled-content>), activated partial thromboplastin time (<jats:styled-content style="fixed-case">aPTT</jats:styled-content>) and modified prothrombin time (<jats:styled-content style="fixed-case">mPT</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Forty‐eight subjects were randomized and treated (apixaban, <jats:italic>n</jats:italic> = 36; placebo, <jats:italic>n</jats:italic> = 12); one subject receiving 2.5 mg twice daily discontinued due to <jats:styled-content style="fixed-case">AEs</jats:styled-content> (headache and nausea). No dose limiting <jats:styled-content style="fixed-case">AEs</jats:styled-content> 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 <jats:italic>vs.</jats:italic> once daily regimens. Clotting times showed dose‐related increases tracking the plasma concentration–time profile.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>