Chloroquine (CQ)(氯奎寧)是一種廣泛使用的抗瘧疾藥物,並具有免疫調節的功能。Hydroxychloroquine (HCQ) (羥氯奎寧)則是chloroquine的同類藥,但服用安全性較高,因此更常被使用來治療瘧疾及自體免疫疾病。過去體外實驗發現HCQ可抑制SARS-CoV複製,近來同樣發現CQ可抑制SARS-CoV-2複製。兩藥物所具的免疫調節作用,也被認為可能可以控制武漢肺炎重症患者體內的細胞激素風暴。為了進一步了解CQ與HCQ的抗SARS-CoV-2能力及臨床使用建議劑量,研究團隊除了進行體外病毒實驗,也使用生理為基礎之藥物動力學模型(Physiologically Based Pharmacokinetic Model, PBPK)分析方法,藉由輸入生理及藥物動力學的參數,預測人體組織可達的藥物濃度,並以實際臨床試驗所得的組織藥物濃度驗證模型正確性,藉此提出藥物的建議使用劑量、頻次及天數。實驗顯示CQ及HCQ都具有不錯的抗SARS-CoV-2能力,但HCQ抗病毒EC50較CQ抗病毒EC50來得更低,表示HCQ更能有效抑制病毒複製。PBPK 模型顯示,相較於CQ,HCQ可達到更高的肺部藥物谷濃度/EC50數值。再者,第1天口服2次400 mg HCQ,第2至5日每天服用2次200 mg HCQ後,第10日時肺部的HCQ濃度仍可維持在治療目標濃度以上。因此,研究團隊認為HCQ是更為優先推薦的COVID-19治療藥物,建議療程則為上述的5日藥物療程。

(財團法人國家衛生研究院 莊淑鈞博士、吳綺容醫師整理)

Background

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) 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 SARS-CoV-2 infected patients. 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 models (PBPK) 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 whilst considering the drug’s safety profile.

Results

Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) 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 three 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.

Author:Xueting Yao, Fei Ye, Miao Zhang, et al.
原文連結:https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998

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