K.H. Liesenfeld, C. Tillmann, I. Troconiz (#), H.G. Schaefer, J. Stangier
Boehringer Ingelheim Pharma GmbH & Co. KG, (#) School of Pharmacy, University of Navarra, Pamplona, Spain
Introduction: The oral direct thrombin inhibitor prodrug dabigatran etexilate is under development for the prevention of deep vein thrombosis in patients at risk of thrombotic events. The effects of the active principle dabigatran (BIBR 953 ZW) on the activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) were assessed in a dose escalation safety study (BISTRO I) involving 289 patients treated with 12.5 to 300 mg dabigatran etexilate B.I.D. and 150 and 300 mg Q.D. for 6 – 10 days.
Methods: Dabigatran plasma concentrations and the pharmacodynamic parameters aPTT and ECT were measured 4 hours after the first dose, before drug administrations (trough), 2 h post dose, and by frequent sampling at steady state. In total, 287 patients were included in the population analysis of aPTT and ECT.
Results: Pharmacodynamic model for aPTT: The relationship of dabigatran plasma concentrations and aPTT was best described by combining an Emax model with a linear model as shown by the following equation: aPTT = BASE + (EMAX*CONC /(EC50+CONC)) + SLOP*CONC Interindividual variability (IIV) was allowed on EMAX, BASE, SLOP and EC50. The typical (population) values of EMAX and BASE itself were a function of time after surgery: EMAX = EMA0 * (1 – (EMMX * TIME/24) / (ET50 + TIME/24)) BASE = BAS0 * (1 – (EMBA * TIME/24) / (ET50 + TIME/24)) The typical estimate of the initial baseline aPTT (BASE, time=0) was 33.4s. The typical values for EMAX (initial) and EC50 were 26.9 s and 94.7 ng/mL, respectively. SLOP, which gives the typical slope of the linear relationship between CONC and aPTT, was 0.0509 s/(ng/mL). This decline in the typical values of EMAX and BASE was modelled by an inhibitory EMAX-model. The half-life (ET50) of the decline was approximately 1.6 days for both EMAX and BASE and the maximum decline about 46.3% for EMAX and 10.2% for BASE, respectively. Pharmacodynamic model for ECT: The relationship of dabigatran plasma concentrations and ECT was described by a linear function: ECT= BASE + SLOP * CONC Interindividual variability was allowed on SLOP (14%) and BASE (8%). The typical (population) values for BASE and SLOP itself were a function of time after surgery. The typical value of the initial baseline ECT was 28 s (BASE, time=0). The decrease in BASE was described by an inhibitory EMAX model (similar to aPTT) with a half-life of baseline decline of 2.9 days and a maximum decline of 17.5%. The typical value of the slope of the plasma concentration-ECT relationship (SLOP) decreased from initially 0.38 s/(ng/mL) to 0.27 s/(ng/mL). The decrease in SLOP was described by a combination of two exponential terms: SLOP = SLO0*EXP(-KM*TIME)+SLOFinal*(1-EXP(-KM*TIME)) The residual variabilities of aPTT and ECT were 7.6 and 6.6%, respectively. The covariate analysis (patient demographics, treatment variables and co- medications) indicated that the model parameters were not affected by any of the tested covariates.
Conclusions: The population pharmacodynamic investigation of the effect of the direct thrombin inhibitor dabigatran revealed a close correlation between drug plasma concentrations and effect on blood coagulation. The relationship between dabigatran plasma concentrations and ECT was linear, whereas the plasma concentration – aPTT relationship was best described by a combined Emax and linear model. The time-dependency in the aPTT- as well as the ECT-model indicates, that for a given dabigatran concentration the observed increase in aPTT and ECT would be larger early after surgery and less at later times. This observation can be rationalised by peri/post surgical effects on hemostasis, e.g. volumes of transfusion administered during surgery.
Reference: PAGE 12 (2003) Abstr 387 [www.page-meeting.org/?abstract=387]
Poster: poster