C. Garnett (1), K.H. Liesenfeld(2), C. Tillmann(2), I. Troconiz(3), H.G. Schaefer(2), J. Stangier(2), H. Lee (1)
(1) Center for Drug Development Science, Georgetown University, Washington, DC; (2) Boehringer Ingelheim Pharma GmbH & Co KG; (3) School of Pharmacy, University of Navarra, Pamplona, Spain
Objectives: To estimate the posterior distribution of the maximum response (Rmax), the minimum response (Rmin), and the area under the response-time curve over 24 h (AURC24h) for the blood coagulation markers ECT and aPTT for 4 doses of dabigatran etexilate (50 mg bid, 150 mg bid, 225 mg bid, and 300 mg qd); and to calculate the power to detect differences in the PD parameters between the qd and the three bid dose groups.
Methods: The simulation platform consisted of a covariate distribution model; a PK model with covariates; PD models for ECT and aPTT; stochastic models for PK and PD parameter uncertainty, interindividual variability and residual error; and a nominal trial execution model consisting of 300 patients per dose group. 100 replications of the simulation model were performed using Trial Simulator®. PD parameters were calculated using model-independent techniques in S-Plus and analyzed with Dunnett’s multiple simultaneous comparisons using the 300 mg qd dose as control. The power was calculated as the number of replicates showing p-value <0.05 between doses and its 95% CI was reported.
Results: The simulated distributions of the covariates, concentrations, ECT, and aPTT were comparable to the observed clinical data. The geometric mean values of baseline-corrected AURC24h for ECT were 202, 614, 925, and 626 sec*h for the 50, 150, 225 mg bid and 300 mg qd dose groups, respectively, and the gCV% ranged from 65 to 73%. For aPTT, the geometric mean values of baseline-corrected AURC24h were 130, 317, 420, and 311 sec*h for the 50, 150, 225 mg bid and 300 mg qd dose groups, respectively, and gCV% ranged from 47 to 158%. Only 1% (95%CI=0-3%) of the replicates showed a significant difference between the 300 mg qd and 150 mg bid dose groups for AURC24h for ECT; similarly, power was 7% (95%CI=2-12%) for aPTT. Rmax for the 300 mg qd dose was similar to the 225 mg bid dose for ECT (power = 17%, 95%CI=13-21%) and for aPTT (power = 12%, 95%CI=6-18%). For both ECT and aPTT, Rmin for the 300 mg qd dose was higher than the 50 mg bid dose (power = 100% and 95%, respectively) and was lower than the 150 mg bid dose (power=100%, for both).
Conclusions: These results suggest the 300 mg qd dose may be therapeutically equivalent to the bid doses. This inference may be tested by incorporating clinical outcome models for deep vein thrombosis and major bleeding into this clinical trial simulation model.
Reference: PAGE 12 (2003) Abstr 388 [www.page-meeting.org/?abstract=388]
Poster: poster