首页|Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model

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Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19).To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens,a PBPK model,with parameterization of drug distribution extrapolated from animal data,was developed to predict human tissue distribution of CQ.The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism.Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships.The model was also validated by clinical data from Chinese patients with COVID-19.The novel PBPK model allows indepth description of the pharmacokinetics of CQ in several key organs (lung,heart,liver,and kidney),and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID,Days 2 -5:500 mg BID,CQ phosphate),patients with moderate COVID-19 (Day 1: 750 mg and 500 mg,Days 2 -3:500 mg BID,Days 4-5:250 mg BID,CQ phosphate),and other vulnerable populations (e.g.,renal and hepatic impairment and elderly patients,Days 1-5:250 mg BID,CQ phosphate).A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

COVID-19Chloroquine phosphatePBPKDosing strategy

Cheng Cui、Miao Zhang、Xueting Yao、Siqi Tu、Zhe Hou、Valerie Sia Jie En、Xiaoqiang Xiang、Jing Lin、Ting Cai、Ning Shen、Chunli Song、Jie Qiao、Shun Zhang、Haiyan Li、Dongyang Liu

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Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China

Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China

Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital,University of Chinese Academy of Sciences (Ningbo No.2 Hospital), Ningbo 315010, China

Department of Respirator, Peking University Third Hospital, Beijing 100191, China

Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital,Beijing 100191, China

Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191,China

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We thank DrsEleanor Howgate and Maurice Dickins for the development of the original chloroquine PBPK base model,and thank Lisa A

2020

药学学报(英文版)

药学学报(英文版)

CSTPCDCSCDSCI
ISSN：
年,卷(期)：2020.10(7)
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