Predicting Fluconazole Drug-Drug Interactions Using a Physiologically-based Pharmacokinetic (PBPK) Model
Received Date: Jun 14, 2022 / Published Date: Jul 14, 2022
Abstract
Aim: Physiologically Based Pharmacokinetic (PBPK) model is developed to (1) simulate clinical trials involving the Drug-Drug Interactions (DDI) between fluconazole and drugs (substrates) metabolized primarily by CYP2C9 and CYP3A, and to (2) support dosing recommendations.
Methods: The plasma-concentration profiles were simulated in virtual individuals for each drug alone and in combination with fluconazole in B2O simulator. The effect of fluconazole on substrates was compared with published clinical data, and dose adjustment was carried out.
Results: The magnitude of inhibition tended to be more pronounced for substrates with predominant CYP3A4 metabolism, for example, lemborexant, than those with dual CYP3A4/2C9 metabolism. The dose of flurbiprofen was adjusted from 50 mg to 25 mg and 20 mg respectively, to counteract the DDI effects caused by fluconazole 200 mg/day and 400 mg/day.
Conclusion: The PBPK model established based on the mechanism of DDI and inhibitor’s effect on enzyme activity can reasonably simulate the effect of fluconazole on drug substrates mainly metabolized by CYP2C9, CYP3A or both.
Keywords: CYP2C9; CYP3A; Inhibitor; Fluconazole; Pharmacokinetic/pharmacodynamic model; Drug-drug interaction; Candidemia
Citation: Li X, Wu K, Zhou Z, Jia R, Zhao Y, et al. (2022) Predicting Fluconazole Drug-Drug Interactions Using a Physiologically-based Pharmacokinetic (PBPK) Model. J Infect Dis Ther 10: 504. Doi: 10.4172/2332-0877.1000504
Copyright: © 2022 Li X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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