Characterization of the time course of carbamazepine deinduction by an enzyme turnover model.
OBJECTIVE
Carbamazepine is a potent inducer of drug metabolizing enzymes, which results in a number of clinically significant drug-drug interactions. Deinduction occurs when long-term carbamazepine therapy is discontinued. The goal of this study was to develop a population pharmacokinetic model to describe the time course of carbamazepine deinduction.


METHODS
Stable-labelled carbamazepine was administered intravenously on three occasions during the deinduction period to 15 patients with epilepsy for whom carbamazepine therapy was being discontinued. Data were analysed using a nonlinear mixed-effects model (NONMEM). An enzyme turnover model consisting of a one-compartment model linked with a hypothetical enzyme compartment was applied to characterize the time course of carbamazepine deinduction. Model evaluation was performed using the bootstrap approach and a visual predictive check.


RESULTS
In the final model, the deinduction process was accomplished by decreasing the rate of enzyme synthesis, resulting in a decrease in the relative amount of enzymes. The estimated rate constant for enzyme degradation was 0.00805 h-1, corresponding to a half-life of the combined enzymes of 86.1 hours (3.6 days).


CONCLUSIONS
An enzyme turnover model adequately characterized the experimental data. Based on the predicted enzyme half-life from the final model, the deinduction process should be completed within 2 weeks after carbamazepine therapy is terminated.
Punyawudho
Baralee
B
Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota 55414, USA.
Cloyd
James C
JC
Leppik
Ilo E
IE
Ramsay
R Eugene
RE
Marino
Susan E
SE
Pennell
Page B
PB
White
James R
JR
Birnbaum
Angela K
AK
D000328:Adult; D002220:Carbamazepine / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D013997:Time Factors
D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A