Characterization of the Time Course of Carbamazepine Deinduction by an Enzyme Turnover Model

• Published in: Clinical pharmacokinetics Vol. 48; no. 5; pp. 313 - 320
• Main Authors: Punyawudho, Baralee, Cloyd, James C., Leppik, Ilo E., Ramsay, R. Eugene, Marino, Susan E., Pennell, Page B., White, James R., Birnbaum, Angela K.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2009; Adis International; Springer Nature B.V
• Subjects: Adult; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Carbamazepine - blood; Carbamazepine - metabolism; Carbamazepine - therapeutic use; Cytochrome P-450 CYP3A - metabolism; Epilepsy - blood; Epilepsy - drug therapy; Epilepsy - enzymology; Female; General pharmacology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate - physiology; Models, Biological; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Original Research Article; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Time Factors; Enzyme Production; Population Pharmacokinetic Model; Enzyme Degradation; Carbamazepine; Trigeminal Neuralgia; Human; Nervous system diseases; Enzyme; Epilepsy; Exploration; Anticonvulsant; Tricyclic compound; Metabolism; Cerebral disorder; Characterization; Mood stabilizer; Central nervous system disease; Turnover; Models; Pharmacokinetics; Dibenzazepine derivatives
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/00003088-200948050-00003

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.