使用基于全身生理的抗精神病药物奎硫平的药代动力学模型预测肝病患者速释片和缓释片的药代动力学

IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Ji-Hun Jang, Seung-Hyun Jeong
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引用次数: 0

摘要

虽然喹硫平代谢在肝脏中广泛发生,建议肝病患者谨慎给药,但缺乏根据肝病严重程度调整喹硫平临床剂量的药物计量学研究。本研究旨在建立一个基于生理的全身药代动力学(WB-PBPK)模型来解释喹硫平PK的个体间变异性,并定量预测肝病患者的PK。建立的WB-PBPK模型很好地描述了健康人群中不同喹硫平方案的PK特征。PK预测也适用于精神分裂症患者(与健康受试者无显著差异)。对于相同总剂量的喹硫平,与健康受试者相比,肝脏疾病患者的速释(IR)和缓释(ER)片均显示暴露量显著增加,清除率显著降低。该模型显示,肝病患者多次服用IR片250 mg /天3次或ER片800 mg /天1次后,稳态血浆喹硫平浓度超过了通常的治疗范围。因此,喹硫平IR片或ER片的剂量可根据肝脏疾病的严重程度减少0.10-0.50倍,使平均稳态血药浓度接近治疗范围。喹硫平的WB-PBPK模型能够根据IR或ER配方和肝脏疾病严重程度定量预测PK。这项研究的结果为改善喹硫平的治疗使用提供了有用的数据,使剂量选择基于配方和肝脏疾病的严重程度。图形抽象
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetic Prediction of Immediate- and Extended-Release Tablets for Patients with Liver Disease Using Whole Body Physiologically-Based Pharmacokinetic Modeling for the Antipsychotic Drug Quetiapine

Although quetiapine metabolism occurs extensively in the liver and careful dosing is recommended in patients with liver disease, there has been a paucity of pharmacometric studies to adjust the clinical dose of quetiapine according to liver-disease severity. This study aimed to establish a whole-body, physiologically-based pharmacokinetic (WB-PBPK) model to explain interindividual variability in quetiapine PK and quantitatively predict PK in patients with liver disease. The developed WB-PBPK model well described the PK characteristics of different quetiapine regimens in healthy populations. The PK predictions could also be applied to patients with schizophrenia (without significant differences from healthy subjects). For the same total dose of quetiapine, both immediate-release (IR) and extended-release (ER) tablets showed significantly increased exposure and decreased clearance in patients with liver disease compared to healthy subjects. The model showed that steady-state plasma quetiapine concentrations exceeded the usual therapeutic range after multiple doses of IR tablets 250 mg three times daily or ER tablets 800 mg once daily in patients with liver disease. Therefore, the doses of quetiapine IR or ER tablets could be reduced by 0.10–0.50 times depending on liver-disease severity, so that mean steady-state plasma concentrations could be positioned near the therapeutic range. WB-PBPK modeling for quetiapine enabled quantitative prediction of PK according to IR or ER formulation and liver-disease severity. The results of this study provide useful data for improving the therapeutic use of quetiapine by enabling dose selection based on formulation and liver-disease severity.

Graphical Abstract

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来源期刊
AAPS PharmSciTech
AAPS PharmSciTech 医学-药学
CiteScore
6.80
自引率
3.00%
发文量
264
审稿时长
2.4 months
期刊介绍: AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.
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