Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics
Open Access
- 21 May 2020
- journal article
- research article
- Published by Wiley in Clinical Pharmacology & Therapeutics
- Vol. 108 (4), 775-790
- https://doi.org/10.1002/cpt.1909
Abstract
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against 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, EC90 values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentrations (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 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 Cmax/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 EC50 by 7.8‐ and 1.5‐fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.Keywords
This publication has 95 references indexed in Scilit:
- Inhibition of STAT3 by Niclosamide Synergizes with Erlotinib against Head and Neck CancerPLOS ONE, 2013
- Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical StudyBioMed Research International, 2013
- Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral EffectsPLoS Pathogens, 2012
- New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus MefloquineAntimicrobial Agents and Chemotherapy, 2010
- Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy VolunteersAntimicrobial Agents and Chemotherapy, 2009
- Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at the Post-translational LevelOnline Journal of Public Health Informatics, 2009
- Pharmacokinetics and Tissue Distribution of Anidulafungin in RatsAntimicrobial Agents and Chemotherapy, 2008
- Effect of Rifampin on Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Healthy VolunteersAntimicrobial Agents and Chemotherapy, 2006
- AnidulafunginDrugs, 2004
- STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENTThe Lancet, 1986