Pharmacokinetic modelling to enable early attrition of repurposed antiviral drug combination candidates with a high likelihood of failure in COVID-19

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Pharmacokinetic modelling to enable early attrition of repurposed antiviral drug combination candidates with a high likelihood of failure in COVID-19

Lorraine Ralph¹, Olivier Touzelet², Ahlam Ali², Joanne Sharp¹, Richard Walker², James Stewart³, Miles Carroll⁴, Ultan Power² and Andrew Owen¹

¹Centre of Excellence for Long-acting Therapeutics, University of Liverpool; ²School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast; ³Infection Biology & Microbiomes, University of Liverpool; ⁴Pandemic Sciences Institute, Medical Sciences Division, University of Oxford

Introduction: COVID-19 remains a concern in some patient population groups such as those who are immunosuppressed. While antiviral monotherapy is available, development of combination therapy could offer improved efficacy while reducing the risk of developing resistance. Repurposing drugs already approved or at late stage development can speed up the time to market, reduce risk of failure and decrease costs relative to more traditional development programmes. To avoid unnecessary waste of resources when selecting drugs for potential repurposing, it is essential to rule out compounds that are unlikely to achieve efficacious concentrations at safe doses in patients.

Aim: To conduct pharmacokinetic modelling and simulations to predict drug concentrations in patients for drug combinations identified as having activity against SARS-CoV-2 in vitro.

Methods: Literature searches were performed using PubMed to identify clinical concentration–time profiles for drug combinations determined as having synergistic activity against SARS-CoV-2 in Calu-3 and AAT cells. Published data were digitalised using WebPlotDigitizer and formatted for pharmacokinetic analysis. One-, two- and three- compartment models were fitted to the data as appropriate using R. Selected models were used to simulate plasma concentration-time profiles in a patient population (n = 1000) at dose regimens considered to have an acceptable safety profile. Simulated plasma concentrations were compared with the in vitro calculated EC90 values for SARS-CoV-2.

Results: In vitro studies identified 37 drug combinations with synergistic efficacy against SARS-CoV-2. Five drugs could not undergo PK modelling due to unavailability of clinical concentration data in the literature. Two drugs had been withdrawn from the market due to adverse events so did not undergo any further PK evaluation. Three drugs were eliminated from further evaluation due to other reasons (formulation challenges, prior clinical testing, etc.). Of the remaining combinations, PK simulations identified 18 combinations where at least one drug would not achieve efficacious systemic concentrations in patients.

Conclusions: Modelling and simulations of pharmacokinetic data used in conjunction with EC90 values obtained from in vitro studies can optimize the selection of lead candidates for drug repurposing by eliminating those with a high certainty of failure. Early attrition enables resources to be dedicated to candidates more likely to succeed.