Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban

AIM: To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). METHOD: In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio INR and arachidonic acid-induced platelet aggregation AAI-PA). Adverse events, bleeding time and routine safety assessments were also evaluated. RESULTS: Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation SD) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 1.0 vs. 2.7 0.7 IU ml(-1) , consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean SD bleeding time was higher following co-administration (9.1 4.1 min) compared with either agent alone (5.8 2.3 and 6.9 2.6 min for apixaban and naproxen, respectively). CONCLUSION: Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen.