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

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,∞), 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.

Keywords: P-glycoprotein; anticoagulant; apixaban; clinical pharmacology; factor Xa; naproxen drug interaction.

Figure 1

Study design and participant flow. The shaded area between days 7 and 10 shows where subjects were allowed to leave the clinical facility. The study concluded on day 14 when subjects were discharged

Figure 2

Mean concentration–time profiles for (A) apixaban and (B) naproxen. , apixaban alone; , co-administration of apixaban and naproxen; , naproxen alone; , co-administration of apixaban and naproxen

Figure 3

Relationship between anti-Xa activity and apixaban concentration 3 h after treatment. Values , apixaban alone; , naproxen alone; , co-administration of apixaban and naproxen