ALBERT

Description: Abstract 4175 Introduction 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. Methods 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. Results 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. AUC0-24 and Cmax values were increased ≤16% for clopidogrel and ≤13% for the carboxylic acid metabolite. Although aspirin AUC0-24 and Cmax 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. Conclusion This study demonstrated that no clinically meaningful pharmacodynamic or pharmacokinetic interactions were observed when TAK-442 was co-administered with aspirin or clopidogrel. Disclosures: 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.

Description: Abstract 3326 Introduction: TAK-442 is an oral direct factor Xa (fXa) inhibitor currently in clinical development for the prevention of venous and arterial thromboembolism. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling is a powerful tool for predicting efficacy and safety in drug development programs. The derivation of PK-PD exposure metrics in patients allows exploration of the key descriptors of the clinical response and can lead to more informed dose selection. The development of PK-PD models using response biomarkers relevant to anticoagulation (e.g., prothrombin time [PT] and fXa inhibition) may predict the antithrombotic effects of the drug in this patient population. Methods: Population PK-PD methods (non-linear mixed effects modeling program) were used to derive individual exposure parameters, such as area under the plasma concentration time curve (AUC), maximum concentration (Cmax) and minimum concentration at the end of a dose interval (Cmin) and the corresponding PD parameters (PT and fXa inhibition) for all patients receiving TAK-442 in a Phase II dose ranging trial. Patients received 40 or 80 mg p.o. once daily or 10, 20, 40, or 80 mg p.o. twice daily (n=150 per group) for thromboprophylaxis after elective total knee arthroplasty. Logistical regression analysis was used to explore the relationships between the derived PK-PD exposure metrics and the primary efficacy (composite of all-cause mortality, symptomatic and asymptomatic deep vein thrombosis [DVT], and symptomatic pulmonary embolism [PE]) and safety endpoints (combined major, minor, and clinically significant non-major bleeding events). Results: The PK of TAK-442 were found to be linear over the dose range studied, with no significant time dependencies. The logistical regression analysis identified significant relationships between increasing exposure and a decrease in the probability of the primary efficacy endpoint, with the strongest relationships observed for Cmax and AUC (P-value of ≤0.001 and 0.03, respectively) and fXa inhibition Emax (P-value of ≤0.001). For every 100 ng/mL increase in Cmax, the odds of having a composite efficacy event were reduced by 10.1% (odds ratio=0.899, 95% confidence interval=0.843, 0.958). In contrast, exploration of the safety endpoint for bleeding did not identify any significant relationships between any of the exposure metrics (Cmax, Cmin, and AUC) or the corresponding PD metrics for fXa inhibition or PT. Conclusions: The PK and PD of TAK-442 in patients undergoing total knee arthroplasty were found to be dose-dependent and predictable. Significant relationships were identified between the PK and PD exposure metrics and the reduction in the primary efficacy endpoint. At the dose ranges studied, no relationship was found between any of the PK-PD exposure metrics and the bleeding endpoint. In conclusion, key predictors of clinical efficacy were identified, whereas no exposure metrics correlated with increased bleeding events. Disclosures: Stringer: Takeda Global Research & Development Centre, Ltd.: Employment. Ploeger:Takeda Global Research & Development Center, Inc.: Consultancy. Wood:Takeda Global Research & Development Centre, Ltd.: Employment. Moneuse:Takeda Global Research & Development Centre, Ltd.: Employment. Kawamura:Takeda Global Research & Development Center, Inc.: Employment. Kupfer:Takeda Global Research & Development Center, Inc.: Employment. Spaeder:Takeda Pharmaceuticals International: Employment. Scott:Takeda Global Research & Development Centre, Ltd.: Employment.