Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics
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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% (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 (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 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.
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SciScore for 10.1101/2020.04.16.20068379: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Candidate Analysis: To identify compounds and their relevant potency and pharmacokinetic data, we performed a literature search on PubMed, Google Scholar, BioRxiv, MedRxiv, and ChemRxiv. PubMedsuggested: (PubMed, RRID:SCR_004846)Google Scholarsuggested: (Google Scholar, RRID:SCR_008878)BioRxivsuggested: (bioRxiv, RRID:SCR_003933)Graphs were then re-plotted in SigmaPlot 14.0 (Systat Software, Inc.) and curves were fitted to confirm EC50 values and determine EC90 values. SigmaPlotsuggested: (SigmaPlot, RRID:SCR_003210)Results from OddPub: We did not detect open data. We also did not detect …
SciScore for 10.1101/2020.04.16.20068379: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Candidate Analysis: To identify compounds and their relevant potency and pharmacokinetic data, we performed a literature search on PubMed, Google Scholar, BioRxiv, MedRxiv, and ChemRxiv. PubMedsuggested: (PubMed, RRID:SCR_004846)Google Scholarsuggested: (Google Scholar, RRID:SCR_008878)BioRxivsuggested: (bioRxiv, RRID:SCR_003933)Graphs were then re-plotted in SigmaPlot 14.0 (Systat Software, Inc.) and curves were fitted to confirm EC50 values and determine EC90 values. SigmaPlotsuggested: (SigmaPlot, RRID:SCR_003210)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations of this analysis: This study represents the first holistic view of drugs with reported activity against SARS-CoV-2 in the context of their achievable pharmacokinetic exposure in humans. While the analysis does provide a basis to rationally selected candidates for further analysis, there are some important limitations. Firstly, Cmax was the only pharmacokinetic parameter that was universally available for all of the candidate drugs, but Cmin values are generally accepted as a better marker of efficacy since they represent the lowest plasma concentration over the dosing interval. However, Cmax was only used to assess whether plasma concentration would exceed those required at any point in the dosing interval, and this was followed by a more in-depth analysis of the most promising candidates. Secondly, an EC50 value only equates to a concentration required to suppress 50% of the virus, and data were unavailable to calculate EC90 values for some of the drugs. EC90 values are a preferred marker of activity because the slope of the concentration-response curve can vary substantially between different molecules and between different mechanisms of action. Although EC90 were not calculable for all drugs the authors deemed it appropriate to deprioritise molecules not achieving EC50 at Cmax in this analysis. Thirdly, the reported antiviral activities were conducted under different conditions (Table 1) and in several cases varied between the same molecule assessed in differen...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04323527 Completed Chloroquine Diphosphate for the Treatment of Severe Acute Re… NCT04333628 Terminated Chloroquine for Mild Symptomatic and Asymptomatic COVID-19 NCT04316377 Active, not recruiting Norwegian Coronavirus Disease 2019 Study NCT04316377 Active, not recruiting Norwegian Coronavirus Disease 2019 Study NCT04333225 Completed Hydroxychloroquine in the Prevention of COVID-19 Infection i… NCT04307693 Terminated Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in P… NCT04307693 Terminated Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in P… NCT04331834 Completed Pre-Exposure Prophylaxis With Hydroxychloroquine for High-Ri… NCT04331834 Completed Pre-Exposure Prophylaxis With Hydroxychloroquine for High-Ri… NCT04255017 Recruiting A Prospective/Retrospective,Randomized Controlled Clinical S… NCT04315948 Active, not recruiting Trial of Treatments for COVID-19 in Hospitalized Adults NCT04315948 Active, not recruiting Trial of Treatments for COVID-19 in Hospitalized Adults NCT04292730 Completed Study to Evaluate the Safety and Antiviral Activity of Remde… NCT04292899 Completed Study to Evaluate the Safety and Antiviral Activity of Remde… NCT04257656 Terminated A Trial of Remdesivir in Adults With Severe COVID-19 NCT04257656 Terminated A Trial of Remdesivir in Adults With Severe COVID-19 NCT04252664 Suspended A Trial of Remdesivir in Adults With Mild and Moderate COVID… NCT04252664 Suspended A Trial of Remdesivir in Adults With Mild and Moderate COVID… NCT04310228 Recruiting Favipiravir Combined With Tocilizumab in the Treatment of Co… NCT04319900 Recruiting Clinical Trial of Favipiravir Tablets Combine With Chloroqui… NCT03800173 Completed A Study to Evaluate the Single Dose Safety, Tolerability and… NCT04341493 Recruiting Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19 NCT04341493 Recruiting Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19 NCT04343248 Recruiting Trial to Evaluate the Efficacy and Safety of Nitazoxanide (N… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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