Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Acta Pharmacol Sin. 2018 Mar;39(3):472-481. doi: 10.1038/aps.2017.153. Epub 2017 Nov 9.
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 E 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 E 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.
地塞米松（DEX）是 CYP3A 的底物。然而，当 DEX 持续给药时，CYP3A 的活性可能会被 DEX 诱导，导致 DEX 的自动诱导和时间依赖性药代动力学（随时间清除的药代动力学）。在这项研究中，我们在人乳腺癌异种移植裸鼠中研究了单次或多次给药后 DEX 的药代动力学特征，并建立了基于半机理的药代动力学/药效学（PK/PD）模型，用于描述 DEX 的时间依赖性 PK 及其抗癌作用。小鼠口服给予单次或多次剂量（8mg/kg）的 DEX，并使用 LC-MS/MS 评估 DEX 的血浆浓度。每天记录肿瘤体积。基于实验数据，建立了一个具有一级吸收和时间依赖性清除的两室模型，并通过 sigmoid E 方程对清除的时间依赖性进行建模。此外，还建立了一个基于半机理的 PK/PD 模型，其中整合了 DEX 对其代谢酶 CYP3A 的自动诱导作用，并使用 E 方程描述药物效力。PK/PD 模型进一步用于预测在考虑或不考虑自动诱导作用时的药物疗效，这进一步揭示了在最终 PK/PD 模型中添加自动诱导作用的必要性。这项研究建立了一个基于半机理的 PK/PD 模型，用于描述乳腺癌异种移植小鼠中 DEX 的时间依赖性药代动力学及其抗癌作用。该模型可作为未来临床前或临床研究中调整或优化 DEX 剂量的参考。
