Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

被引：102

作者：

Arshad, Usman ^{[1
]}

Pertinez, Henry ^{[1
]}

Box, Helen ^{[1
]}

Tatham, Lee ^{[1
]}

Rajoli, Rajith K. R. ^{[1
]}

Curley, Paul ^{[1
]}

Neary, Megan ^{[1
]}

Sharp, Joanne ^{[1
]}

Liptrott, Neill J. ^{[1
]}

Valentijn, Anthony ^{[1
]}

David, Christopher ^{[1
]}

Rannard, Steve P. ^{[2
]}

O'Neill, Paul M. ^{[2
]}

Aljayyoussi, Ghaith ^{[3
]}

Pennington, Shaun H. ^{[3
]}

Ward, Stephen A. ^{[3
]}

Hill, Andrew ^{[1
]}

Back, David J. ^{[1
]}

Khoo, Saye H. ^{[1
]}

Bray, Patrick G. ^{[4
]}

Biagini, Giancarlo A. ^{[3
]}

Owen, Andrew ^{[1
]}

机构：

[1] Univ Liverpool, Dept Mol & Clin Pharmacol, Mat Innovat Factory, Liverpool, Merseyside, England

[2] Univ Liverpool, Dept Chem, Liverpool, Merseyside, England

[3] Univ Liverpool Liverpool Sch Trop Med, Dept Trop Dis Biol, Liverpool, Merseyside, England

[4] Pat Bray Elect, Wigan, England

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2020年 / 108卷 / 04期

基金：

英国医学研究理事会; 英国工程与自然科学研究理事会;

关键词：

RESISTANT PLASMODIUM-FALCIPARUM; STEADY-STATE PHARMACOKINETICS; PROTEASE INHIBITOR NELFINAVIR; TISSUE DISTRIBUTION; HIV; NITAZOXANIDE; INDOMETHACIN; CHLOROQUINE; TIPRANAVIR; MEFLOQUINE;

D O I：

10.1002/cpt.1909

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

There is a rapidly expanding literature on thein vitroantiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90) values recalculated fromin vitroanti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (C-max) at an approved dose in humans (C-max/EC(90)ratio). Only 14 of the 56 analyzed drugs achieved a C-max/EC(90)ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated to derive a lung C-max/half-maximal effective concentration (EC50) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. Nitazoxanide and sulfadoxine also exceeded their reported EC(50)by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC(90)values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

引用

页码：775 / 790

页数：16

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[1] Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2 kinase PKR [J].