S. Gisbert, I. Gueorguieva, L. Aarons and M. Rowland
. Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, England.
Aim:Previously we developed a WBPBPK (Whole Body Physiologically Based Pharmacokinetic) model for diazepam in rat incorporating variability in drug dependant parameters (clearance, coefficients of partition: Kp) as well as in drug independant parameters (physiological parameters: volumes, blood flows) which was used for extrapolation to man. The aim of the present work was to extend the WBPBPK model developed for diazepam (DZ) to two other benzodiazepines: flunitrazepam (FZ) and midazolam (MZ). For each of these three molecules we used the models to investigate the impact of different values of intrinsic clearance (from the literature, from human PK data and from in vitro studies).
Materials:In vivo studies in rats: The drugs were administered i.v. to each of 24 male Sprague-Dawley rats at a dose of 1 and 2 mg/kg. In vivo studies in man: iv PK data provided by Hoffman-La Roche. In vitro studies in man: Human liver microsomes were isolated from sections of 12 individual humans livers. Clearances for DZ and MZ were determined via substrate depletion and for FZ via metabolite formation. Studies with testosterone were performed to study the activation of CYP3A4(1).
Methods:Modelling of rat and man plasma data to obtain estimates of the total clearances was performed in NONMEM using bi and three exponentials. Due to limited renal excretion total clearance was assumed equal to hepatic clearance. Using the well-stirred model estimates of the intrinsic clearance for the drugs were obtained.Optimisation of the Kp values of the PBPK model was performed using MATLAB 6.1. Using weighted least squares the obtained Kp values were used for susequent simulations in rat and man.
Results and Discussion:Physiological variability contributed considerably to the overall variability particularly at early times. At later times variability was determined by intrinsic clearance. The quality of the predictions was highly dependent on the population estimate of intrinsic clearance used in the simulations. Failure to adequately account for both variability in physilogical and drug dependent parameters compromises the ability to predict PK variability in man from in vitro and animal tissue data.
References:(1) Heteroactivation of CYP3A4 substrates: Impact of intrinsic clearance and interindividual variability. H.C. Rawden A. Tindall, D. Hallifax, B. Houston (2001) Drug Metabolism Review 33(1):211.
Reference: PAGE 12 (2003) Abstr 401 [www.page-meeting.org/?abstract=401]
Poster: poster