A Quantitative Enterohepatic Circulation Model
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Background and Objective
Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t1/2). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of tesofensine and meloxicam to various extents.
Two studies were investigated retrospectively for model development and model evaluation. Twentyone healthy subjects received a single 6-hour infusion of tesofensine (0.3, 0.6, 0.9, 1.2 mg) in a double-blind, randomized, placebo-controlled, single rising-dose study. Twelve healthy subjects were treated in a randomized, crossover study with meloxicam 30 mg as a single dose given intravenously (bolus) either alone or concomitantly with cholestyramine. The EHC model was developed based on data from the tesofensine study, where EHC is suspected. Model evaluation was performed with data from the meloxicam trial. Modelling and simulation analyses were performed using the software programs NONMEM, SAS and Berkeley Madonna.
Plasma concentration-time profiles of tesofensine were best described by a three-compartment model (absorption, central and gallbladder) with first-order elimination. The release of the bile compartment was controlled by a sine function model, switching the bile compartment periodically on and off using the actual clock time as the control element. A four-compartment model (absorption, central, peripheral and gallbladder) with first-order elimination and the sine function for gallbladder control described the meloxicam data best. Coadministration of cholestyramine resulted in a predicted 56% withdrawal of meloxicam from the EHC process causing a reduction in the t1/2 from ∼19 hours to ∼12 hours.
A quantitative EHC model was successfully developed that was capable of describing the multiple peaks in plasma concentration-time profiles of tesofensine and meloxicam very well. Additionally, the model successfully quantified the observed results for an interruption of the meloxicam EHC. The model offers an in silico method to support an EHC hypothesis using standard pharmacokinetic data and might help to guide dosing recommendations of compounds undergoing EHC.
KeywordsInterindividual Variability Central Compartment Meloxicam Clock Time Visual Predictive Check
The authors wish to thank Ole Østerberg for his very helpful contribution. This study was financially supported by Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, Germany. Charlotte Kloft received research funding from Boehringer Ingelheim Pharma. Thorsten Lehr, Alexander Staab, Christiane Tillmann, Dirk Trommeshauser, Hans-Guenter Schaefer are current employees at Boehringer Ingelheim Pharma GmbH and Co. KG.
- 2.Gabrielsson J, Weiner D. Pharmacokinetic/pharmacodynamic data analysis: concepts and applications. 3rd ed. Stockholm: Taylor & Francis, 2000Google Scholar
- 23.Beal SL, Sheiner LB. NONMEM users guide: conditional estimation methods. San Francisco (CA): University of California, 1998Google Scholar
- 27.Montgomery DC, Peck EA, Vinters HV. Introduction to linear regression analysis. Chichester (NY): Wiley, 2001Google Scholar