Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Xu, Tianhong; Gao, Xuejuan; Wu, Zengbin; Selinger, Douglas W.; Zhou, Zichen

doi:10.1101/2020.04.01.017624

Cited by 51 publications

(66 citation statements)

References 52 publications

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“…We identified 14 key studies that detailed the antiviral activity of 72 compounds [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Table 1.…”

Section: Identified Papers and Methodsmentioning

confidence: 99%

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

Pertinez

Box

et al. 2020

Preprint

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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 (EC50), 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 EC90 value for each drug. EC90 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/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 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 (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 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 EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 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 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.

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“…We identified 14 key studies that detailed the antiviral activity of 72 compounds [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Table 1.…”

Section: Identified Papers and Methodsmentioning

confidence: 99%

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

Pertinez

Box

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The level of cell infection was determined by luciferase activity in the cell lysates of infected cells at 48 h post-infection (p.i.). INDO was found to possess a remarkable antiviral activity, reducing viral particle production dose-dependently with an IC50 of ~1μM, and selective index of 500, and caused a dramatic reduction relative light unit to zero at 48 h p.i, in VERO E6 cells [16].…”

Section: Anti-coronavirus Activity In-vitromentioning

confidence: 99%

“…In the second study [16], the % of recovery in CCoV-infected dogs treated orally with INDO 1 mg/kg body weight was evaluated. Dogs treated with ribavirin (a broad-spectrum antiviral drug with efficacy against RNA and DNA viruses) were used as a control group.…”

Section: Anti-coronavirus Activity In Ccov-infected Dogmentioning

confidence: 99%

“…The Weibull model was finally retained as it showed better performance in fitting either the viral load or the rate of recovery data. Figure 2 (panel A) shows the observed and model-predicted rate of recovery [16] and viral load data [11] in CCoV infected dogs. Panel B shows the curvilinear relationship between viral load and rate of recovery estimated using the Weibull model predictions.…”

Section: Modeling Viral Load and Rate Of Recovery In Dogmentioning

confidence: 99%

“…INDO, at concentrations in the low micromolar range, activates PKR leading to an interferon-and dsRNA-independent phosphorylation of the eukaryotic initiation factor-2 α-subunit [14], shutting off viral protein translation and blocking viral replication [15]. A recent study conducted in-vitro and in CCoV infected dogs showed that INDO has also a direct and potent antiviral activity against the SARS CoV-2 pseudovirus [16]. In this study the rate of recovery in CCoV-infected dogs treated orally with INDO 1 mg/kg body weight was also evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Model Based Approach for Estimating the Dosage Regimen of Indomethacin a Potential Antiviral Treatment of Patients Infected with SARS CoV-2

Goméni¹,

Xu²,

Gao³

et al. 2020

Preprint

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To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach.A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect needs to be further assessed in a prospective clinical trial.

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

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

141

148

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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 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.

show abstract

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Cited by 51 publications

References 52 publications

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

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

Model Based Approach for Estimating the Dosage Regimen of Indomethacin a Potential Antiviral Treatment of Patients Infected with SARS CoV-2

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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