Abstract
Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.
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Acknowledgements
The authors appreciate the technical support of LC-MS/MS from Prof Jun LI (School of Pharmaceutical Science, Peking University Health Science Center). This study was supported by the projects of National Natural Science Foundation of China (NSFC) (Grant No 81273583, 81473277 and 81673500). The first three authors are supported by Pfizer Scholarships for Pharmacometrics.
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Supplementary Figure S1
The goodness-of-fit plots of the time-dependent PK model. (TIF 5174 kb)
Supplementary Figure S2
The goodness-of-fit plots of the integrated PK/PD model. (TIF 5129 kb)
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Li, J., Chen, R., Yao, Qy. et al. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model. Acta Pharmacol Sin 39, 472–481 (2018). https://doi.org/10.1038/aps.2017.153
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DOI: https://doi.org/10.1038/aps.2017.153
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