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

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Frost C, Shenker A, Gandhi MD, Pursley J, Barrett YC, Wang J, Zhang D, Byon W, Boyd RA, LaCreta F

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

Br J Clin Pharmacol. 2014 Oct;78(4):877-85. doi: 10.1111/bcp.12393.

PubMed ID

24697979 [ View in PubMed

]

Abstract

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,infinity), 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Naproxen	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Naproxen	P-glycoprotein 1	Protein	Humans	No	Inhibitor	Details

Drug Interactions

Drugs	Interaction
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