Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

Autor: Kanefendt F; Clinical Pharmacology, Bayer AG, Berlin, Germany., Dallmann A; Bayer HealthCare SAS, Loos, France, on behalf of Bayer AG, Pharmacometrics/Modeling and Simulation, Systems Pharmacology & Medicine - PBPK, Germany., Chen H; Clinical Pharmacology Asia, Bayer AG, China., Francke K; Translational Medicine, Bayer AG, Germany., Liu T; Clinical Pharmacology Asia, Bayer AG, China., Brase C; Translational Medicine, Bayer AG, Germany., Frechen S; Systems Pharmacology & Medicine - PBPK, Bayer AG, Germany., Schultze-Mosgau MH; Clinical Pharmacology, Bayer AG, Berlin, Germany.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 May; Vol. 115 (5), pp. 1025-1032. Date of Electronic Publication: 2024 Jan 08.
DOI: 10.1002/cpt.3151
Abstrakt: In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC( 0-∞ )) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.
(© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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