Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.
Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.
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DOI：
10.1111/bcp.14619
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发表时间：
2021-04
影响因子：
3.4
通讯作者：
Owen A
中科院分区：
文献类型：
--
作者：
Rajoli RKR;Pertinez H;Arshad U;Box H;Tatham L;Curley P;Neary M;Sharp J;Liptrott NJ;Valentijn A;David C;Rannard SP;Aljayyoussi G;Pennington SH;Hill A;Boffito M;Ward SA;Khoo SH;Bray PG;O'Neill PM;Hong WD;Biagini GA;Owen A
严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）已被宣布为全球大流行病，需要紧急治疗和预防策略。硝唑尼特是一种驱虫药，已被证明对SARS-CoV-2具有体外活性。本研究使用基于生理学的药代动力学（PBPK）建模，以告知能够维持血浆和肺替唑尼特暴露高于报告的SARS-CoV-2 EC90的硝唑尼特的最佳剂量。根据健康个体在进食和不进食的情况下接受500 - 4000 mg单次和多次给药的现有药代动力学数据，对全身PBPK模型进行了验证。使用经验证的模型来预测预期在> 90%的模拟群体中将替唑尼特血浆和肺浓度维持在EC 90以上的剂量。PopDes用于估计未来临床试验的最佳稀疏采样策略。根据报告的人体药代动力学成功验证了PBPK模型。该模型预测空腹状态下的最佳剂量为1200 mg QID、1600 mg TID和2900 mg BID，与食物同服时为700 mg QID、900 mg TID和1400 mg BID。对于BID方案，估计最佳稀疏采样策略为给药后0.25、1、3和12小时。PBPK模型预测的替唑尼特浓度内剂量的硝唑尼特已经给予人类以前。报告的给药策略为设计硝唑尼特治疗或预防SARS-CoV-2感染的临床试验提供了合理的依据。目前计划在无缝I/IIa期AGILE试验中研究一致的更高剂量的硝唑尼特。
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS‐CoV‐2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS‐CoV‐2 EC90. A whole‐body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS‐CoV‐2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
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影响因子：
4.4
作者：
Koszalka P;Tilmanis D;Hurt AC
通讯作者：
Hurt AC
影响因子：
7.6
作者：
Cao J;Forrest JC;Zhang X
通讯作者：
Zhang X
影响因子：
4.9
作者：
Dang, Wen;Xu, Lei;Pan, Qiuwei
通讯作者：
Pan, Qiuwei
影响因子：
5.6
作者：
Miner, Kent;Labitzke, Katja;Sullivan, John K.
通讯作者：
Sullivan, John K.
DOI：
10.1016/s1473-3099(14)70717-0
发表时间：
2014-07
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Haffizulla J;Hartman A;Hoppers M;Resnick H;Samudrala S;Ginocchio C;Bardin M;Rossignol JF;US Nitazoxanide Influenza Clinical Study Group
通讯作者：
US Nitazoxanide Influenza Clinical Study Group