C.Tillmann, I.F. Trocóniz (#), J. Stangier, K. H. Liesenfeld, H.G. Schaefer
Boehringer Ingelheim Pharma GmbH & Co KG, (#) School of Pharmacy, University of Navarra, Pamplona, Spain
Introduction: Dabigatran etexilate (BIBR 1048) is an orally available double prodrug of the active principle dabigatran (BIBR 953 ZW), which exerts potent anticoagulant and antithrombotic activity. Dabigatran etexilate is currently in phase II clinical development.
Objectives: Study 1160.11 (BISTRO I) was the first clinical trial with Dabigatran etexilate in the target population (i.e. patients undergoing primary elective total hip replacement). The aim of the analysis was to develop a population pharmacokinetic (PK) model in order to describe the dose- concentration relationship of BIBR 953 ZW and to characterise both, the inter- individual (IIV) and residual variability as well as to quantify the relationship between covariates and PK model parameters.
Methods: A PK population model was developed using NONMEM (Version 5) on a UNIX (HP UX ver.11.0) platform. A total of 4604 plasma concentrations obtained from 287 patients after once or twice daily oral dosing for up to 10 days after surgery in the dose range 12.5, 25, 50, 100, 150, 200 and 300 mg were available for the analysis. Structural PK models were parameterised in terms of apparent volumes of distribution, clearances for distribution and elimination and absorption rate constants. Twenty-five covariates containing patient demographic factors and treatment variables were tested to evaluate their influence on the pharmacokinetic parameters.
Results: Pharmacokinetics of dabigatran were best described by a two compartment body model with first order absorption and first order elimination. Inclusion of a lag time was also required. The rate constant of drug absorption (KA ) during the first day of treatment was significantly lower (p<0.01) compared to days 2 to 10. In addition, the data supported the estimation of different degrees of IIV KA and apparent plasma clearance (CL/F) between day 1 and days 2 to 10 after surgery. The following estimates for IIV were obtained: Day 1, 109 % (CL/F), days 2 to 10, 30 % (KA), 46 % (CL/F). Estimates of residual variability differed also between the two occasions (day 1 vs. days 2-10): 67% vs 36%. Age and serum creatinine (SCR) influenced significantly KA (p<0.01), whereas gastrin (GAST), and creatinine clearance (CRCL), only for days 2-10, effected CL/F. The typical values for KA for a 67 years old patient with SCR of 0.964 mg/dL were 0.022 h-1 and 0.093 h-1 on day 1 and days 2 to 10, respectively. The typical value for CL/F on day 1 for a patient with GAST of 34.58 pmol/L was 70.87 L/h, whereas on days 2 to 10 the typical CL/F was 106.2 L/h for a patient with GAST of 34.58 pmol/L and CRCL of 76.16 mL/min. The typical estimates (SE) for the apparent volumes of distribution of the central and peripheral compartments were 30.8 L (17%) and 136 L (42%), respectively. The typical value (SE) of intercompartmental clearance, was 13.6 L/h (36%). Inclusion of the above mentioned covariates resulted in a 12, 4 and 8 % (absolute) reduction in the initial unexplained interindividual variability found in KA and CL/F (day 1, days 2 to 10), respectively.
Conclusions: These results show that during the first 24 hours after surgery the pharmacokinetics of dabigatran are different compared to the following days. This is most likely due to alterations in gastric motility and gastric pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days the PK behaviour of dabigatran is less variable. Several covariates influencing pharmacokinetic parameters were identified. However, their impact on biomarkers for bleeding (aPTT, ECT) will be evaluated integrating pharmacokinetics with pharmacodynamics.
Reference: PAGE 12 () Abstr 386 [www.page-meeting.org/?abstract=386]
Poster: poster