2005 - Pamplona - Spain

PAGE 2005: poster
Thorsten Lehr

Evaluation of an enterohepatic circulation model: predicting the influence of cholestyramine on the pharmacokinetics of meloxicam

T. Lehr (1), C. Tillmann (2), A. Staab (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

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Objectives & Background: Concentration-time profiles of drugs undergoing enterohepatic circulation (EHC) are often associated with multiple peak phenomena and a longer apparent half-life. Basic models describing EHC were reported in the literature [1]. Lehr et al. developed an EHC model considering the clock time as a control variable for the gall bladder emptying [2]. The objective of this study was to apply and evaluate the model by using data of a drug undergoing EHC (meloxicam [3]). Evaluation was to be performed by a) fitting the model to observed meloxicam plasma concentrations and b) by predicting the effect of interrupting the EHC on pharmacokinetics by co-administration of cholestyramine.

Methods: Plasma concentration-time profiles of 12 subjects treated with 30 mg meloxicam  intravenously (bolus) either alone or concomitantly treated with 4 g t.i.d cholestyramine for four days were analysed. A three compartment model (central, peripheral and bile) with first order elimination was used to describe the data. The release of the bile compartment was controlled by a sine function model, switching the bile compartment periodically on and off. Interruption of EHC was mimicked by setting the rate transfer constant from bile to central compartment to zero.

Results: The model successfully described the plasma concentration-time profiles of all subjects including the multiple peak phenomena. Clearance and half-life of meloxicam after intravenous administration were determined to be 0.367 L/h and 20.1 h respectively. Simulating the interruption of the EHC resulted in a predicted increased clearance of 0.616 L/h and a shortened half-life of 11.0 h. These model-predicted values are in close agreement with the observed results from the compartmental analysis [3].

Conclusion: EHC of meloxicam could be successfully described by the model proposed by Lehr et al. Interruption of the EHC could be reliably predicted. Slight overestimation of clearance and half-life might be caused by an incomplete interruption of the EHC with cholestyramine.
The model might serve as a tool to describe the pharmacokinetics of drugs undergoing EHC and to assess the impact of interrupting the EHC e.g. by co-medication with cholestyramine or charcoal.

[1] Roberts M. et al., Clin. Pharmacokinet., 41, 751-790
[2] Lehr. et al., PAGE Meeting 2004, www.page-meeting.org
[3] Busch U. et al., Eur. J. Clin. Pharmacol., 48, 269-272, 1995

Reference: PAGE 14 (2005) Abstr 766 [www.page-meeting.org/?abstract=766]