Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban.
OBJECTIVE
To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor).


METHODS
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).


CONCLUSIONS
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.
At time of Research, Bristol-Myers Squibb, Princeton, NJ.
Charles
C
Frost
Andrew
A
Shenker
Mohit D
MD
Gandhi
Janice
J
Pursley
Yu Chen
YC
Barrett
Jessie
J
Wang
Donglu
D
Zhang
Wonkyung
W
Byon
Rebecca A
RA
Boyd
Frank
F
LaCreta
D000328:Adult; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D009288:Naproxen / Q000494:pharmacology*; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011728:Pyridones / Q000493:pharmacokinetics* / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D009288:Naproxen
P-glycoprotein; anticoagulant; apixaban; clinical pharmacology; factor Xa; naproxen drug interaction