In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
复制标题
DOI：
10.1093/cid/ciaa237
复制
发表时间：
2020-08-01
影响因子：
11.8
通讯作者：
Liu, Dongyang
中科院分区：
文献类型：
--
作者：
Yao, Xueting;Ye, Fei;Liu, Dongyang
背景资料。严重急性呼吸综合征冠状病毒2(SARS-CoV-2)于2019年首次暴发，随后在全球范围内传播。氯喹曾被零星用于治疗SARS-CoV-2感染。羟基氯喹的作用机制与氯喹相同，但其更易耐受的安全性使其成为治疗疟疾和自身免疫性疾病的首选药物。我们认为，羟氯喹的免疫调节作用也可能有助于控制SARS-CoV-2危重患者晚期发生的细胞因子风暴。目前，尚无证据支持使用羟氯喹治疗SARS-CoV-2感染。用SARS-CoV-2感染的Vero细胞检测氯喹和羟基氯喹的药理活性。通过整合两种药物的体外数据，分别建立了基于生理的药物动力学(PBPK)模型。利用PBPK模型，模拟5种不同给药方案下肺液中羟氯喹的浓度，在考虑药物安全性的前提下，探索最有效的给药方案。羟氯喹(EC_(50)=0.72 mU/M)的体外药效高于氯喹(EC_(50)=5.47 mU/M)。根据PBPK模型的结果，对于SARS-CoV-2感染，建议负荷剂量为每日两次口服400 mg硫酸羟氯喹，然后每日两次口服维持量200 mg，连续4天，提前5天每日两次口服500 mg，效力达到磷酸氯喹的3倍。体外实验发现，羟基氯喹对SARS-CoV-2的抑制作用强于氯喹。
Background. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.Methods. The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2-infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug's safety profile.Results. Hydroxychloroquine (EC50 = 0.72 mu M) was found to be more potent than chloroquine (EC50 = 5.47 mu M) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.Conclusions. Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.