Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China.
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, 999077, China.
Eur J Clin Pharmacol. 2021 Apr;77(4):583-593. doi: 10.1007/s00228-020-03032-6. Epub 2020 Nov 13.
Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure-efficacy/safety relationship and provide a basis for a possible dosing regimen optimization.
In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications.
A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml).
Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics-pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.
氯喹（CQ）已被重新用于治疗 2019 年冠状病毒病（COVID-19）。了解 COVID-19 患者的药代动力学（PK）对于研究其暴露-疗效/安全性关系以及为可能的剂量方案优化提供基础至关重要。
在这项研究中，我们使用基于人群的荟萃分析方法来建立一个群体 PK 模型，以描述 COVID-19 患者的 CQ PK。一项开放标签、单中心研究（伦理审查批准号：PJ-NBEY-KY-2020-063-01）评估了 CQ 在 COVID-19 患者中的安全性、疗效和 PK。将 50 名接受 COVID-19 治疗的患者的稀疏 PK 数据（每天两次接受 500mg 磷酸氯喹，共 7 天）与来自 18 篇文献的其他 CQ PK 数据相结合。
一个具有一级口服吸收和一级消除以及吸收滞后的两室模型最好地描述了数据。吸收速率（ka）估计为 0.559h，吸收滞后时间（ALAG）估计为 0.149h。表观清除率（CL/F）和表观中心分布容积（V2/F）分别为 33.3l/h 和 3630l。表观分布清除率（Q/F）和外周室分布容积（Q3/F）分别为 58.7l/h 和 5120l。根据磷酸氯喹的五种给药方案模拟的 CQ 浓度均在安全范围内（400ng/ml）。
使用 COVID-19 患者的 PK 参数进行基于模型的模拟表明，目前推荐的给药方案下的浓度低于不良反应的安全范围，这表明这些给药方案通常是安全的。该推导的群体 PK 模型应允许评估 CQ 单独或与其他药物联合用于治疗 COVID-19 时的 PK-PD 关系。
