Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics
Usman Arshad, Henry Pertinez, Helen Box, Lee Tatham, Rajith K R Rajoli, Paul Curley, Megan Neary, Joanne Sharp, Neill J Liptrott, Anthony Valentijn, Christopher David, Steve P Rannard, Paul M O’neill, Ghaith Aljayyoussi, Shaun H Pennington, Stephen A Ward, Andrew Hill, David J Back, Saye H Khoo, Patrick G Bray, Giancarlo A Biagini, Andrew Owen
Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1909
There is a rapidly expanding literature on the in vitro antiviral 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% (EC 90 ) values recalculated from in vitro anti-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 (K p U lung ) was also simulated to derive a lung C max /half-maximal effective concentration (EC 50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavirboosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC 50 . 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.
SUPPORTING INFORMATION Supplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
ACKNOWLEDGMENTS The authors thank Nathan Morin from Alberta Health Services for being proactive in making them aware of previously published data for indomethacin. The authors also thank Articulate Science for publication support. CONFLICT OF INTEREST D.J.B. has received honoraria or advisory board payments from AbbVie, Gilead, ViiV, Merck, Janssen, and educational grants from AbbVie, Gilead, ViiV, Merck, Janssen, and Novartis. A.O. and S.P.R. are Directors of Tandem Nano Ltd. A.O. has received research funding from ViiV, Merck, Janssen, and consultancy from Gilead, ViiV and Merck not related to the current paper. P.O.N. is currently engaged in a collaboration with Romark LLC but this interaction did not influence the prioritization or conclusions in the current paper. All other authors declared no competing interests for this work.
AUTHOR CONTRIBUTIONS All authors wrote the paper. A.O. designed the research. U.A., H.B., L.T., H.P., and A.O. performed the research. R.R., H.P., U.A., and A.O. analyzed the data.
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