A team of scientists from the Pennsylvania State University, USA, recently analyzed the pharmacodynamics and pharmacokinetics of antiviral drug remdesivir using computational models.

Based on the study findings, which are yet to be peer-reviewed, the scientists recommend that for effective inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, remdesivir should be used with other antiviral medicines, or its dosing regimen should be optimized to improve bioavailability. The study is currently available on the medRxiv* preprint server.

Background

With the progression of the coronavirus disease 2019 (COVID-19) pandemic, which has already infected 178 million people and claimed 3.8 million lives globally, many therapeutic, as well as prophylactic interventions, have been developed to tackle viral transmission and reduce disease-related morbidity and mortality. Among therapeutics, anti-SARS-CoV-2 monoclonal antibodies and repurposed antiviral medicines have shown potential benefits in treating moderate to severe COVID-19 patients.

Based on the promising outcomes in early human clinical trials, remdesivir has received emergency use approval from various healthcare authorities, including the European Medical Association (EMA) and the US Food and Drug Administration (FDA). At the initial phase of the pandemic, studies investing therapeutic efficacy of remdesivir have shown that this repurposed antiviral medicine is capable of shortening the time to recovery and reducing the symptom intensity in in-hospitalized patients with severe COVID-19. However, later on, some studies have shown limited or no efficacy of remdesivir in treating COVID-19 patients. Multiple clinical studies are currently ongoing to investigate whether the therapeutic efficacy of remdesivir can be improved by using it with other antiviral medicines.

In the current study, the scientists have conducted pharmacokinetic and pharmacodynamic modeling to predict the optimal dosing regimen for remdesivir. Regarding pharmacokinetics, it is known that upon administration, prodrug remdesivir is converted to its active triphosphate metabolite GS-443902 in cells, which has a longer half-life than remdesivir.

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The scientists have developed a novel pharmacodynamic model based on the binding affinity of active remdesivir for its target RNA-dependent RNA polymerase in SARS-CoV-2. They have further used the model to evaluate the therapeutic efficacy of the current remdesivir dosing regimen, as well as to predict the optimal dosing regimen with improved efficacy and reduced toxicity. Importantly, they have examined whether the proposed dose regimen can increase the risk of developing drug resistance in SARS-CoV-2.

Important observations

Based on the computational analysis, the scientists hypothesized that about 88% and 96% drug–target binding (target occupancy) in the upper and lower respiratory tracts, respectively, is required for effective inhibition of viral replication. However, with the current dosing regimen, remdesivir failed to achieve accurate target occupancy and thus, could not inhibit viral replication in both upper and lower respiratory tracts. Taken together, these findings indicate that the antiviral ineffectiveness of remdesivir in the current scenario is largely due to suboptimal dosing.

Using a nonlinear model equation, the scientists predicted a drug infusion rate of approximately 168 mg/hour that maximized the intracellular bioavailability of remdesivir active metabolite. This means, for an infusion regimen of 1 hour, a total drug dose of 168 mg is sufficient to provide the highest drug efficacy; whereas, for an infusion regimen of 2 hours, approximately 336 mg of remdesivir is required to get the maximum drug efficacy.

Using the proposed infusion rate, they simulated a 5-day treatment regimen, which resulted in improved suppression of SARS-CoV-2 infection. Specifically, they observed that infusion of 500 mg of remdesivir over 3 hours resulted in inhibition of viral replication only in the upper respiratory tract at peak concentrations. In contrast, the effective concentration required for viral inhibition could not be achieved in the lower respiratory tract. However, for viral suppression in the lower respiratory tract, they needed to infuse 1350 mg of remdesivir over 8 hours. Taken together, these observations indicate that by carefully monitoring the safety profile, both infusion rate and duration can be modified to increase remdesivir efficacy.

Regarding drug resistance, previous studies have shown that mutations in RNA-dependent RNA polymerase can reduce SARS-CoV-2 sensitivity to remdesivir. However, these mutations do not influence viral fitness within host cells. This indicates that resistant mutants carrying such mutations can readily emerge in remdesivir-treated patients and can frequently transmit between patients.

Given these observations, the scientists predicted the remdesivir concentrations that specifically select for resistance (resistance selection window). Specifically, they observed that the highest treatment regimen (1350 mg for 8 hours) used in this study resulted in an intracellular active remdesivir concentration of 250 µM in the second half of the therapy, which is sufficient to suppress resistance in the upper respiratory tract. However, for the current remdesivir dosing regimen, they noticed that the currently used drug dose strongly selects for resistance to remdesivir and that resistant mutants must have significantly lower fitness to suppress resistance.      

Study significance

The study highlights the significance of dosing rate and duration in improving the antiviral efficacy of remdesivir. Based on the findings, the scientists suggest that remdesivir should to used with other antiviral medicines, or its dosing regimen should be optimized to reduce the risk of drug resistance.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.