Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad, Usman ORCID: 0000-0003-1586-1885, Pertinez, Henry, Box, Helen, Tatham, Lee, Rajoli, Rajith KR ORCID: 0000-0002-6015-5712, Curley, Paul ORCID: 0000-0003-4596-2708, Neary, Megan, Sharp, Joanne, Liptrott, Neill ORCID: 0000-0002-5980-8966, Valentijn, Anthony
et al (show 11 more authors) (2020) Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics. Clinical Pharmacology and Therapeutics. 2020.04.16.20068379-.

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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 ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC 50 ), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC 90 value for each drug. EC 90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC 90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC 90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (K p U lung ) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC 50 as a better indicator of potential human efficacy (lung Cmax/EC 90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC 50 . This analysis was not possible for nelfinavir because insufficient data were available to calculate K p U lung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC 50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are 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 lung, in order to maximise the potential for success of proposed human clinical trials.

Item Type: Article
Uncontrolled Keywords: Lung, 5 Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, 3 Good Health and Well Being
Depositing User: Symplectic Admin
Date Deposited: 27 Aug 2020 14:26
Last Modified: 14 Mar 2024 17:39
DOI: 10.1101/2020.04.16.20068379
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