Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model

• 来源期刊: 中国药理学报（英文版）
• 关键词: dexamethasone pharmacokinetic/pharmacodynamic model auto-induction time-dependent clearance breast cancer
• 年，卷（期）: 2018,（3）
• 页码范围: 472-481
• 页数: 10页
• 语种: 英文
• DOI: 10.1038/aps.2017.153

摘要

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 timedependent 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 semimechanism-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.