| Title | Characterization of the time course of carbamazepine deinduction by an enzyme turnover model. | | Author(s) | Punyawudho B, Cloyd JC, Leppik IE, Ramsay RE, Marino SE, Pennell PB, White JR, Birnbaum AK | | Institution | Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA. | | Source | Clin Pharmacokinet 2009; 48(5):313-20. | | Abstract | 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. 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(R)). 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. 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). 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19566114 |
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