pd-0348292 and Thromboembolism

PD 0348292 is an oral, selective, direct and reversible factor Xa inhibitor. This was an adaptive dose-ranging study evaluating a 100-fold PD 0348292 dose range in subjects undergoing total knee replacement (TKR).. To assess the efficacy and safety of a dose range of PD 0348292 relative to enoxaparin for the prevention of venous thromboembolism (VTE).. Extensive dose-response modeling and trial simulations were used to select the PD 0348292 dose range for the Phase 2 study. Subjects were randomized to a blinded PD 0348292 dose (0.1 mg qd to 10 mg qd) or open-label enoxaparin (30 mg bid) for 6-14 days after TKR surgery. Efficacy was assessed by mandatory bilateral venography. Results were analyzed using a dose-response modeling approach.. Observed VTE frequency ranged from 1.4-37.1% across PD 0348292 doses and was 18.1% for enoxaparin. The PD 0348292 dose-response relationship for VTE was statistically significant (P < 0.0001). The dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention was estimated to be 1.16 mg (95% CI = 0.56 mg, 2.41 mg) qd. Total bleeding ranged from 4.9% to 13.8% across PD 0348292 doses and was 6.3% with enoxaparin. The dose-response relationship for total bleeding was not statistically significant (P = 0.2464). Overall, PD 0348292 and enoxaparin were well tolerated.. Characterization of the dose-response relationship for VTE and bleeding using an adaptive Phase 2 study design provided a strong quantitative basis for Phase 3 dose selection.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Arthroplasty, Replacement, Knee; Computer Simulation; Dose-Response Relationship, Drug; Enoxaparin; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Probability; Pyridones; Pyrrolidines; Thromboembolism; Treatment Outcome