K.-H. Liesenfeld (1), J. Stangier (1), C. Garnett (2), C. Tillmann (1), I. Troconiz (3), H. Lee (2), H.G. Schaefer (1)
(1) Boehringer Ingelheim Pharma GmbH & Co KG; (2) Center for Drug Development Science, Georgetown University, Washington, DC; (3) School of Pharmacy, University of Navarra, Pamplona, Spain
Objectives: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism following total hip and knee replacement. In order to optimise dose selection for phase III and to explore the effect of renal impairment PK/PD and CTS was used to analyse phase II data on dabigatran plasma concentrations, ecarin clotting time (ECT), incidence of venous thromboembolism (VTE) and bleeding events.
Methods: Study 1: A multicentre, open-label, dose escalation study with 314 patients and oral doses of 12.5, 25, 50, 100, 150, 200 and 300 mg bid or 150 and 300 mg od for a total of 6-10 days. Study 2: A multi-centre, parallel-group, double-blind study in 1973 patients with oral dosing of 50, 150, and 225 mg bid or 300 mg od or 40 mg enoxaparin for a total of 6-10 days .
Results: A two-compartment body model with first order absorption and elimination described the dose-exposure relationship well. Total body clearance was dependent on creatinine clearance.
The relationship between dabigatran plasma concentrations (CONC) and ECT was linear: ECT=BASE + SLOP* CONC. The typical values for BASE (baseline) and SLOP (slope) itself were a function of time after surgery. CTS was used to investigate the impact of renal impairment. A relationship of the incidence of bleeding events and VTE for the 50, 150, and 225 mg bid and 300 mg od dose groups of study 2 with dabigatran exposure was developed. Subsequently, the dose-exposure-effect models were used to explore different study designs for phase III clinical trials. Â
Conclusions: Population PK/PD-Modelling and clinical trial simulation was valuable in understanding the dose-exposure-effect relationship, exploring covariate effects and optimising trial designs.
Reference: PAGE 14 () Abstr 787 [www.page-meeting.org/?abstract=787]
Poster: poster