A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam.
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 (t((1/2))). 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.


METHODS
Two studies were investigated retrospectively for model development and model evaluation. Twenty-one 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.


RESULTS
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 t((1/2)) from approximately 19 hours to approximately 12 hours.


CONCLUSIONS
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.
Lehr
Thorsten
T
Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
Staab
Alexander
A
Tillmann
Christiane
C
Trommeshauser
Dirk
D
Schaefer
Hans-Guenter
HG
Kloft
Charlotte
C
D000328:Adult; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004764:Enterohepatic Circulation / Q000187:drug effects / Q000502:physiology*; D005069:Evaluation Studies as Topic; D006207:Half-Life; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies; D013843:Thiazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
D019086:Bridged Bicyclo Compounds, Heterocyclic; D013843:Thiazines; D013844:Thiazoles; C518479:Tesofensine; D000077239:Meloxicam
Br J Clin Pharmacol. 2008 Jun;65(6):893-907
18279479
Aliment Pharmacol Ther. 2000 May;14 Suppl 2:2-8
10902995
Arzneimittelforschung. 1997 Mar;47(3):253-8
9105543
J Pharmacokinet Biopharm. 1986 Oct;14(5):539-55
3806375
Eur J Clin Pharmacol. 1995;48(3-4):269-72
7589053
Curr Opin Investig Drugs. 2001 Nov;2(11):1592-4
11763162
Pharm Res. 1992 Feb;9(2):169-77
1553336
J Pharm Pharmacol. 2002 Jul;54(7):929-34
12162711
Dig Dis Sci. 1982 Nov;27(11):1019-24
7140486
Eur J Drug Metab Pharmacokinet. 1993 Oct-Dec;18(4):333-8
8020531
Clin Pharmacokinet. 1999 Feb;36(2):115-26
10092958
Comput Methods Programs Biomed. 2004 Aug;75(2):85-94
15212851
Br J Clin Pharmacol. 2007 Jul;64(1):36-48
17324246
J Pharmacokinet Pharmacodyn. 2008 Apr;35(2):185-202
18197467
Comput Methods Programs Biomed. 1999 Apr;59(1):19-29
10215174
Comput Methods Programs Biomed. 1999 Jan;58(1):51-64
10195646
Clin Ther. 2001 Jun;23(6):871-85
11440287
Clin Pharmacokinet. 2002;41(10):751-90
12162761
Clin Pharmacokinet. 2002;41(6):421-30
12074690
J Pharm Sci. 2002 Aug;91(8):1908-14
12115817
Br J Pharmacol. 2008 Mar;153(5):1072-84
18193075
Br J Rheumatol. 1996 Apr;35 Suppl 1:13-6
8630630
Mov Disord. 2004 Oct;19(10):1183-6
15390018
J Clin Pharmacol. 1997 Jun;37(6):486-95
9208355
J Pharm Sci. 1982 Mar;71(3):297-302
7069584
Eur J Drug Metab Pharmacokinet. 1993 Apr-Jun;18(2):131-9
8243495
J Pharm Pharmacol. 1999 Oct;51(10):1143-8
10579685
Expert Opin Pharmacother. 2005 Oct;6(12):2117-40
16197363
J Pharm Sci. 2005 Apr;94(4):883-92
15736194
Br J Pharmacol. 2008 Jan;153(1):164-74
17982477