Absence of Pharmacodynamic or Pharmacokinetic Interactions When TAK-442, An Oral, Direct Factor Xa Inhibitor, Is Coadministered with Aspirin or Clopidogrel.

TAK-442 is a novel orally active, direct Factor Xa (fXa) inhibitor in clinical development for the prevention of venous and arterial thrombotic disorders. Currently, aspirin and clopidogrel are widely used for platelet inhibition in patients with an increased risk of atherothrombotic events, and it is highly likely that TAK-442 may provide incremental anti-thrombotic benefit when used in conjunction with either of these agents. The primary aim of this study was to evaluate the effect of TAK-442 on inhibition of platelet aggregation by aspirin or clopidogrel.

Healthy male and female (n=77), subjects were randomly assigned to 1 of 2 treatments groups and received either TAK-442 60 mg or placebo twice daily (BID) for 11 days, with the addition of aspirin 162 mg or clopidogrel 75 mg once daily (QD) from days 5 to 11. Pharmacokinetics were assessed for TAK-442 (days 4 and 11), aspirin/salicylic acid (day 11) and clopidogrel/carboxylic acid metabolite (day 11. Inhibition of fXa (Coatest^®) was assessed on day 1 and two hours post dose on days 4 and 11. Platelet aggregation (arachidonic acid-induced for the aspirin group or ADP-induced for the clopidogrel group) was assessed on day -1 and 2 hours post dose on days 4 and 11; bleeding time was assessed on day -1 and 2 hours post dose on day 11.

Inhibition of arachidonic acid-induced platelet aggregation by aspirin was not affected by TAK-442 (71% for aspirin + TAK-442 and 74% for aspirin + placebo) nor was there any clinically significant effect of TAK-442 treatment on the inhibition of ADP-induced platelet aggregation by clopidogrel (56% for clopidogrel + TAK-442 and 67% for clopidogrel + placebo) at 2 hours post dose on day 11. Likewise, co-administration of TAK-442 did not have a clinically significant effect on the pharmacokinetic profiles of aspirin or clopidogrel. AUC_0-24 and C_max values were increased ≤16% for clopidogrel and ≤13% for the carboxylic acid metabolite. Although aspirin AUC_0-24 and C_max were increased 2- to 3-fold with coadministration (90% confidence intervals were: 76.2% to 741.8% and 90.1% to 825.1%, respectively), the proportional exposure was very low and the variability was high; the values for the active metabolite, salicylic acid, were increased less than 20% with coadministration. TAK-442-mediated inhibition of fXa activity and prolongation of PT, and the PK profile of TAK-442, were unaffected by co-administration with aspirin or clopidogrel. Coadministration of TAK-442 resulted in modest increases in mean bleeding time compared to aspirin with placebo (aspirin + TAK-442: 558 sec vs. aspirin + placebo: 392 sec) and to clopidogrel with placebo (clopidogrel + TAK-442: 893 sec vs. clopidogrel + placebo: 829 sec). TAK-442 was well tolerated, with a low and similar frequency of mild bleeding events with or without aspirin or clopidogrel coadministration.

This study demonstrated that no clinically meaningful pharmacodynamic or pharmacokinetic interactions were observed when TAK-442 was co-administered with aspirin or clopidogrel.

Stringer:Takeda Global Research & Development, Inc.: Employment. Scott:Takeda Global Research & Development, Inc.: Employment. Kupfer:Takeda Global Research & Development, Inc.: Employment. Cao:Takeda Global Research & Development, Inc.: Employment. Kawamura:Takeda Global Research & Development, Inc.: Employment.