Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

Abstract

Severe COVID‐19 disease including multisystem inflammatory syndrome (MIS‐C) have been reported in children. This report summarizes development of remdesivir physiologically‐based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. Adult PBPK model was applied to predict pediatric remdesivir and metabolites steady‐state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult Phase 1 exposure data in healthy volunteers who were administered a 200 mg loading dose of remdesivir IV over 0.5 hr on Day 1, then 100 mg daily maintenance doses of remdesivir intravenous (IV) over 0.5 hr starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200 mg loading dose on Day 1 then 100 mg daily maintenance dose starting on Day 2) in pediatric patients ≥40 kg and a weight‐based remdesivir dosage regimen (5 mg/kg loading dose on Day 1 then 2.5 mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 ‐ <40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support RDV as a treatment option during the pandemic.