Co-Administration of YM150, An Oral Direct Factor Xa Inhibitor, and Naproxen Does Not Result In Clinically Relevant Changes to the Pharmacodynamic or Pharmacokinetic Profile of Either Agent

YM150, a potent oral direct factor Xa (FXa) inhibitor, is in development for the prevention of venous thromboembolism after major surgery and of thromboembolic events in subjects with atrial fibrillation. After administration, YM150 is rapidly and extensively metabolized into YM-222714, which predominantly determines antithrombotic effect. Naproxen, a non-steroidal anti-inflammatory drug with antiplatelet properties that inhibits cyclooxygenase (COX)-1 and COX-2 isoenzymes, and similar mode of action drugs will likely be co-prescribed with YM150 in clinical practice. This study assessed the interaction of YM150 and naproxen following co-administration in healthy males.

A Phase I, randomized, open-label, 3-period crossover study (≥14-day washout between periods) compared the pharmacodynamic (PD) and pharmacokinetic (PK) properties of YM150 and naproxen given alone and in combination. Subjects received YM150 60 mg once daily and/or naproxen 500 mg twice daily for 6 and 4 days, respectively. Primary endpoint was change in skin bleeding time (SBT); assessors were blinded to treatment. Change from baseline (BL; pre-dose on Day 1) to 3 h post final dose in SBT was calculated to Day 4 for naproxen alone and Day 6 for YM150 alone and the combination group, thereby reflecting the respective times to achieve steady state (SS). Secondary PD endpoints included minimum FXa activity (FXa_min), maximum prothrombin time (PT_max), maximum activated partial thromboplastin time (aPTT_max) and platelet aggregation. Blood and urine PK parameters (maximum concentration [C_max], time to maximum concentration [t_max], area under the curve [AUC] and renal clearance [CL_R]) and safety were also assessed. Blood samples for PK and PD variables were taken at SS on the final day of dosing (pre-dose and up to 24 h post-dose). Data are presented as arithmetic means.

26 subjects were randomized and received treatment (mean age, 30.4 yrs); 6 subjects prematurely discontinued (consent withdrawal, n=3; adverse event [AE], n=2; protocol violation, n=1). Co-administration of YM150 and naproxen did not result in additive increases in SBT (Table). From BL to SS, mean (standard deviation [SD]) SBT (sec) increased from 317 (89.2) to 430 (111) after YM150 alone, from 306 (79.0) to 621 (230) after naproxen alone and from 332 (84.1) to 721 (259) after combination treatment. YM150 inhibited FXa activity and increased PT_max and aPTT_max; co-administration with naproxen did not influence these outcomes (Table). Naproxen decreased collagen-induced platelet aggregation, with no additive effect when co-administered with YM150 (Table).

The PK of YM-222714 was generally unchanged when YM150 was administered alone or with naproxen (t_max 1.70 vs 1.45 h; C_max 1535 vs 1497 ng/mL; AUC_tau 11,644 vs 11,369 ng·h/mL; CL_R 2.39 vs 3.42 L/h); the PK profile of YM150 itself was similarly unchanged (t_max 1.43 vs 1.17 h; C_max 7.94 vs 8.23 ng/mL; AUC_tau 79.8 vs 66.6 ng·h/mL; CL_R 4.91 vs 6.67 L/h). Naproxen PK were also unchanged when co-administered with YM150. Overall, YM150 alone, naproxen alone and combination treatment were safe and well tolerated. Only one subject experienced AEs considered related to treatment (gingival bleeding and epistaxis); combination treatment was discontinued. One other subject discontinued due to an AE unrelated to study drug (gastroenteritis). No clinically relevant changes in laboratory parameters, vital signs or physical assessments were observed.

Co-administration of YM150 with naproxen did not result in additive increases in SBT or clinically relevant changes in the PD or PK profiles of either agent; the combination was generally safe and well tolerated. Observed changes in FXa activity, PT and aPTT confirm the antithrombotic potency of YM150 and YM-222714, which was unaltered upon co-administration with naproxen. YM150 has no clinically relevant interaction with naproxen.

Heeringa:Astellas Pharma Global Development Europe: Employment. Garcia-Hernandez:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Mol:Astellas Pharma Global Development Europe: Employment. Eltink:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.