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

Abstract

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% (EC90) values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analyzed 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/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 EC50 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 EC90 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.

Thein vitroantiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

“…A recent analysis of drugs proposed for repurposing as SARS-CoV-2 antiviral medicines revealed that very few of the proposed candidates achieved their target concentrations after administration of approved doses to humans [29]. Moreover, there have been several recent calls to integrate understanding of pharmacokinetic principles into COVID-19 drug prioritization[30–32].…”

Tafenoquine inhibits replication of SARS-Cov-2 at pharmacologically relevant concentrations in vitro

“…Briefly, the virus was allowed to adsorb to cell monolayers [moi of 1] in 24-well plates for 1h, then parallel cultures were incubated at 37°C in 5% CO2 for 15, 30, 60 minutes, 2, 4, 6 hours prior to adding 15µM HCQ, 15µM TQ and 5µM RD, or negative control (assay media only). Concentrations were chosen to be approximately 5-fold higher than the EC50 in the 48h YR assay, except that for HCQ this was not possible due to cytotoxicity at concentrations ≥ 50 µM, so TQ and HCQ were [3,18,23]. It is apparent that the lack/modest level of activity of HCQ in both animal models and clinical studies [5,14] was not predicted from VERO cells and evidence of extensive lung penetration of HCQ.…”

Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID‐19 Therapeutic Development

“…Currently, many ongoing trials have focused upon monotherapies that may provide insufficient drug exposures (1). Early HIV in vitro assay testing of antiretroviral compounds relied upon interpretation of in vitro EC 50 (effective concentration causing 50% of the maximal response) as a convenient measure for benchmarking clinical drug exposure.…”

“…Several ad hoc and co-ordinated global screening programmes have been initiated, but with few exceptions (5), emergent literature to date has not robustly integrated an understanding of protein binding into screening and development of drugs for SARS-CoV-2. Indeed, none of the studies cited in a recent review of in vitro data sought to determine protein-adjusted activities using methods developed for other viruses (1). Revisiting the lessons learned over two decades ago in HIV is highly warranted.…”