Abstract
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-ECs). We expect that reaching 90% inhibition (EC) 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.
Highlights
In November 2020, the first ACTT-1 study results were released, showing that the antiviral drug remdesivir had some efficacy in treating COVID19, in shortening the time to recovery in adults who were hospitalized withCOVID-19, and providing evidence of lower respiratory tract infection [1]
Remdesivir had already been granted emergency usage approval by large organizations such as the European Medical Association (EMA) [2] and the US Food and Drug Administration (FDA) [3]. These approvals were granted based largely on evidence that remdesivir successfully prevented disease in rhesus macaques infected with Middle East respiratory syndrome coronavirus (MERS-CoV), which is closely related to SARS-CoV-2, the virus associated with COVID-19 [4], and preliminary ACTT
We develop a novel PK model to describe the distribution in the body of the remdesivir (RDV) prodrug and its active triphosphate metabolite GS-443902 (RDV-TP) only, since the metabolic pathway leading from extracellular RDV to intracellular RDV-TP is not yet confirmed [15,16,17]
Summary
In November 2020, the first ACTT-1 study results were released, showing that the antiviral drug remdesivir (commercial name Veklury) had some efficacy in treating COVID19, in shortening the time to recovery in adults who were hospitalized withCOVID-19, and providing evidence of lower respiratory tract infection [1]. Remdesivir had already been granted emergency usage approval by large organizations such as the European Medical Association (EMA) [2] and the US Food and Drug Administration (FDA) [3] These approvals were granted based largely on evidence that remdesivir successfully prevented disease in rhesus macaques infected with Middle East respiratory syndrome coronavirus (MERS-CoV), which is closely related to SARS-CoV-2, the virus associated with COVID-19 [4], and preliminary ACTT study results showing that remdesivir accelerated recovery from advanced COVID-19 [5]. Despite these positive results, the efficacy of remdesivir remains a topic of debate.
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