Naproxen Has No Relevant Effect on the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor. (2005)

Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. BAY 59-7939 compared favourably with enoxaparin in recent clinical trials of the prevention of venous thromboembolism following major orthopaedic surgery. Possible concomitant medications in patients receiving BAY 59-7939 for either the prevention or treatment of venous thromboembolism include non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. This randomized, two-way crossover study was performed to investigate the influence of naproxen on the safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939 in 11 healthy male subjects. The study included a run-in period with naproxen. Treatments were: naproxen 500 mg on 2 consecutive days (run-in), followed by a 14-day washout period, and then randomization either to BAY 59-7939 15 mg; or to naproxen 500 mg on the first day, and naproxen 500 mg and BAY 59-7939 15 mg on the second day. There was a 14-day washout period between crossovers. BAY 59-7939, naproxen, and the combination were well tolerated. Adverse events (eight in total) were reported by three subjects, and all were mild in intensity; there were no drug-related, treatment-emergent adverse events. BAY 59-7939 significantly inhibited Factor Xa activity by 35%, and prolonged prothrombin time (by 1.4 times baseline [tb]), activated partial thromboplastin time (1.3 tb), and HepTest (1.9 tb), with no influence from naproxen. No interaction was observed with respect to collagen-stimulated platelet aggregation. BAY 59-7939 and naproxen together significantly increased bleeding time compared with BAY 59-7939 alone; however, this difference was small compared with naproxen alone for all but one subject. This indicates that some subjects may be more sensitive to the combined effect of naproxen and BAY 59-7939. However, analysis of patients’ data from clinical trials after major orthopaedic surgery showed similar bleeding risks in patients with and without co-medication with NSAIDs at BAY 59-7939 doses up to 10 mg twice daily. The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for BAY 59-7939 both increased by approximately 10% following co-administration of naproxen; however, this small increase in BAY 59-7939 bioavailability was not considered clinically relevant. In conclusion, there is no relevant interaction between BAY 59-7939 and naproxen, although some individuals may be more sensitive to a combination of these drugs. Initial analysis of data from phase II clinical trials of BAY 59-7939 has shown a similar bleeding risk in patients using NSAIDs concomitantly compared with BAY 59-7939 alone. This will be further substantiated in phase III trials. Parameter Naproxen BAY 59-7939 BAY 59-7939 + naproxen aGeometric mean/geometric coefficient of variation; bMedian relative change from baseline; N=11 for all data Bleeding time (tb)a 1.46/0.583 1.20/0.613 2.17/0.576 Platelet aggregationb 0.052 1.02 0.086 AUC (μg.h/L)a - 1250/28.56 1396/26.30 Cmax (μ g/L)a - 152.9/31.51 165.3/27.69