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Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban
Author(s) -
Frost Charles,
Shenker Andrew,
Gandhi Mohit D.,
Pursley Janice,
Barrett Yu Chen,
Wang Jessie,
Zhang Donglu,
Byon Wonkyung,
Boyd Rebecca A.,
LaCreta Frank
Publication year - 2014
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.12393
Subject(s) - apixaban , pharmacodynamics , pharmacokinetics , naproxen , pharmacology , medicine , rivaroxaban , warfarin , alternative medicine , pathology , atrial fibrillation
Aim To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non‐steroidal anti‐inflammatory drug) and apixaban (an oral, selective, direct factor‐ X a 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‐ X a 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 C max 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‐ X a 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‐ X a activity, INR and inhibition of AAI‐PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen.