K.H. Liesenfeld, EU. Gräfe-Mody, A. Staab, H.G. Schaefer
Boehringer Ingelheim Pharma GmbH & Co. KG
Objectives & Background: A population pharmacokinetic model for an intravenous anticoagulant drug in clinical development that acts as a direct factor IIa and Xa inhibitor was to be developed based on available data from healthy subjects. The model development should include an initial screening for covariates that might influence the pharmacokinetic properties of the drug substance. The purpose of the final model was to simulate and evaluate various scenarios (different dosing schedules, changes in pharmacokinetic parameters) for the further clinical development.
Methods: Pharmacokinetic profiles of 95 subjects from three studies (short and long term infusions with and without loading doses) with 1842 plasma samples were analysed. Sampling for pharmacokinetics was performed before start of infusion, during infusion and serially up to 80 hours after start of infusion. The demographic characteristics age, weight, height and body surface area (BSA) as well as creatinine clearances were to be tested as covariates on the pharmacokinetic parameters. The distribution of the demographic characteristics was narrow due to the inclusion criteria of the studies.
Results: The plasma concentration time profiles were best described by a 4-compartment model with first order elimination from the central compartment. The typical estimates of clearance (CL) and volume of the central compartment (V1) were 8.1Â L/h and 10.0Â L, respectively. The volumes of distribution for the peripheral compartments (V2, V3, V4) ranged from 12.4Â L to 13.6Â L and the corresponding intercompartmental clearances (Q2, Q3, Q4) from 21.4 to 0.691Â L/h. Interindividual variability included in CL, V1, V2 and Q2 was low to moderate (21.9 to 43.7%). CL and thus steady-state concentrations were not influenced by any covariate investigated. Age and height were found to have a statistically significant influence on V2. However, the impact on the plasma concentration time profile was negligible.
Conclusion: A pharmacokinetic model based on all available phase I data is available to simulate and evaluate the influence of dosing schedules and changes of pharmacokinetic parameters (e.g. CL) on the pharmacokinetic profiles of the anticoagulant drug. Steady-state plasma concentrations in healthy subjects are not influenced by age, weight, height, body surface area, or creatinine clearance. However, this finding has to be confirmed in patient populations that will probably exhibit much wider distributions of the covariates tested so far.
Reference: PAGE 13 () Abstr 488 [www.page-meeting.org/?abstract=488]
Poster: poster