Clock time as a control variable for gall bladder emptying in an enterohepatic circulation model
T. Lehr (1), C. Tillmann (2), A. Staab (2), D. Trommeshauser (2), H.G. Schaefer (2), C. Kloft (1)
(1) Dept. Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d.R., Germany
Objectives & Background: Plasma concentration-time profiles of a drug in clinical development showed multiple peak phenomenon as well as a long half-life of about 200 h. Enterohepatic circulation (EHC) is often associated with such observations. In the literature, models are presented by Ezzet et al.  and Funaki  to describe the pharmacokinetics of drugs undergoing EHC. However, these models are limited in the number of gall bladder emptyings. Wajima et al.  proposed an improved model using a periodic sinus function to control gall bladder release. The goal of this study was to apply and optimize the sinus function model to explore whether EHC might be a possible explanation for the specific properties of the compound investigated.
Methods: PK profiles of 47 subjects from three studies (single and multiple oral dosing as well as iv infusion) with 997 plasma samples were analyzed. Sampling times ranged up to 1084 h after administration. The data were best described by a two compartmental model (central and bile) with first order absorption and first order elimination. The release of the bile compartment was controlled by a sinus function model, switching the bile compartment periodically on and off. Several modified sinus functions were tested and applied to each study separately as well as to the combined studies.
Results: Implementation of clock time rather than relative time from administration in the sinus function model a) was found to be a pre-requisite for successful application of the EHC model. The model described the plasma concentration-time profiles of all studies adequately. The frequency of the gall bladder emptying was found to be similar across the three studies. A study specific time parameter (TDEL) had to be implemented, to account for the different administration times of the studies.
Conclusion: The model presented by Wajima et al. has the limitation that the on- and offset of the gall bladder emptying do not occur at the same time points of a day. Thus, a successful application of this model to drugs with a long half-life and a resulting long sampling schedule over weeks is difficult.
By implementation of the clock time the sinus function is reset every day resulting in a stabilized model. In consequence, this model accounts for a similar gall bladder emptying rhythm every day. The model presented can explain multiple peak phenomenon and a long half-life.
OMEGA = period of the sinus function
CLOCK = clock time
TDEL = start time difference of the sinus function period for a particular study
 Ezzet F. et al., Clin. Ther., 23, 871-885, 2001
 Funaki T., J. Pharm. Pharmacol., 51, 1143-1148, 1999
 Wajima T. et al., J. Pharm. Pharmacol., 54, 924-934, 2002