A mechanism‐based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID‐19 treatment in humans

Hanafin, Patrick O.; Jermain, Brian; Hickey, Anthony; Kabanov, Alexander V.; Kashuba, Angela D. M.; Sheahan, Timothy P.; Rao, Gauri G.

doi:10.1002/psp4.12584

Cited by 25 publications

(26 citation statements)

References 41 publications

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“…Remdesivir is a prodrug which is metabolized into a nucleoside triphosphate that irreversibly bonds with the RdRp of SARS-CoV-2, blocking viral transcription after cell entry ( Shannon et al, 2020 ; Hanafin et al, 2021 ). It is used clinically for the treatment of COVID-19 patients, but its efficacy is limited ( Beigel et al, 2020 ; Goldman et al, 2020 ; Spinner et al, 2020 ) and its mechanism of action does not address the cytokine storm that also accompanies the disease progression of COVID-19 ( McElvaney et al, 2020 ).…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

et al. 2021

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Remdesivir, a prodrug targeting RNA-dependent-RNA-polymerase, and cyclosporine, a calcineurin inhibitor, individually exerted inhibitory activity against human coronavirus OC43 (HCoV-OC43) in HCT-8 and MRC-5 cells at EC50 values of 96 ± 34 ∼ 85 ± 23 nM and 2,920 ± 364 ∼ 4,419 ± 490 nM, respectively. When combined, these two drugs synergistically inhibited HCoV-OC43 in both HCT-8 and MRC-5 cells assayed by immunofluorescence assay (IFA). Remdesivir and cyclosporine also separately reduced IL-6 production induced by HCoV-OC43 in human lung fibroblasts MRC-5 cells with EC50 values of 224 ± 53 nM and 1,292 ± 352 nM, respectively; and synergistically reduced it when combined. Similar trends were observed for SARS-CoV-2, which were 1) separately inhibited by remdesivir and cyclosporine with respective EC50 values of 3,962 ± 303 nM and 7,213 ± 143 nM by IFA, and 291 ± 91 nM and 6,767 ± 1,827 nM by a plaque-formation assay; and 2) synergistically inhibited by their combination, again by IFA and plaque-formation assay. Collectively, these results suggest that the combination of remdesivir and cyclosporine merits further study as a possible treatment for COVID-19 complexed with a cytokine storm.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

et al. 2021

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“…It is common practice to extrapolate from mouse models to humans, and this approach is very helpful if the target tissue is not easily accessible in human patients (e.g., the lungs) but can be obtained from animal models. Indeed, this approach was taken in Hanafin et al [ 45 ], aiming to identify improved RDV dosing strategies. Their allometry-based modeling predicted that intravenously-delivered RDV could not achieve 90% maximal inhibitory concentration, as measured in vitro, of unbound remdesivir in human plasma.…”

Section: Discussionmentioning

confidence: 99%

“…Based on our pharmacokinetic model, which is calibrated to RDV-TP concentrations in blood (PBMC) and not lung tissue, we expect that the current standard dosing regimen fails to suppress viral replication in both the upper and the lower respiratory tracts. Lung tissue concentrations are likely even lower, such that our estimates are conservative [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?

Conway

Wiesch

2021

Pharmaceutics

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The antiviral remdesivir has been approved by regulatory bodies such as the European Medicines Agency (EMA) and the US Food and Drug administration (FDA) for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose–activity relationships. Here, we employ a computational model that allows drug efficacy predictions based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby describe a drug regimen that may select for resistance. Our results differ from predictions using prodrug dose–response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in the lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend more clinical trials with dosing regimens that substantially increase the levels of RDV-TP and/or pair remdesivir with companion antivirals.

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“…The ongoing pandemic is considered as the toughest one that the 21st century witnessed until now [1]. Therefore, there is an urgent need of medicines, although there are FDA-approved medications such as dexamethasone, which might be beneficial for patients in the critical condition [2], nafomastat [3,4], remdesivir [5,6] etc., and the latter was found ineffective with less or no complete recovery [7]. Therefore, the scientific community has been trying to make new medicines and vaccines to fight COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Niclosamide–Clay Intercalate Coated with Nonionic Polymer for Enhanced Bioavailability toward COVID-19 Treatment

Piao

Rejinold

et al. 2021

Polymers

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Niclosamide (NIC), a conventional anthelmintic agent, is emerging as a repurposed drug for COVID-19 treatment. However, the clinical efficacy is very limited due to its low oral bioavailability resulting from its poor aqueous solubility. In the present study, a new hybrid drug delivery system made of NIC, montmorillonite (MMT), and Tween 60 is proposed to overcome this obstacle. At first, NIC molecules were immobilized into the interlayer space of cationic clay, MMT, to form NIC–MMT hybrids, which could enhance the solubility of NIC, and then the polymer surfactant, Tween 60, was further coated on the external surface of NIC–MMT to improve the release rate and the solubility of NIC and eventually the bioavailability under gastrointestinal condition when orally administered. Finally, we have performed an in vivo pharmacokinetic study to compare the oral bioavailability of NIC for the Tween 60-coated NIC–MMT hybrid with Yomesan®, which is a commercially available NIC. Exceptionally, the Tween 60-coated NIC–MMT hybrid showed higher systemic exposure of NIC than Yomesan®. Therefore, the present NIC–MMT–Tween 60 hybrid can be a potent NIC drug formulation with enhanced solubility and bioavailability in vivo for treating Covid-19.

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A mechanism‐based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID‐19 treatment in humans

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 25 publications

References 41 publications

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?

Niclosamide–Clay Intercalate Coated with Nonionic Polymer for Enhanced Bioavailability toward COVID-19 Treatment

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