Background and 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. Patients and 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). Conclusion: 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.
Bibliographical noteFunding Information:
Dr Baralee Punyawudho now works for the Department of Pharmacy Practice, Chulalongkorn University, Bangkok, Thailand. This work was supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke grant nos. P50-NS16308 NCRR-M01-RR00400, M01-RR00039 and M01-RR16587. Drs James Cloyd, Ilo Leppik and Angela Birnbaum have received a grant and consulting fees and have a royalty agreement with Ovation Pharmaceuticals. Ovation is developing an injectable carbamazepine formulation using, in part, data generated from NIH studies they directed. The other authors have no conflicts of interest to declare that are directly relevant to the content of this study.