Article date: October 2014
By: Charles Frost, Andrew Shenker, Mohit D. Gandhi, Janice Pursley, Yu Chen Barrett, Jessie Wang, Donglu Zhang, Wonkyung Byon, Rebecca A. Boyd, Frank LaCreta, in Volume 78, Issue 4, pages 877-885
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.
DOI: 10.1111/bcp.12393
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