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Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19
Author(s) -
Lutz Justin D.,
Mathias Anita,
German Polina,
Pikora Cheryl,
Reddy Sunila,
Kirby Brian J.
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2176
Subject(s) - covid-19 , pharmacokinetics , selection (genetic algorithm) , pharmacology , coronavirus infections , medicine , computational biology , virology , biology , computer science , artificial intelligence , outbreak , infectious disease (medical specialty) , disease
Severe coronavirus disease 2019 (COVID‐19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically‐based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The 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 I exposure data in healthy volunteers who were administered a 200‐mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100‐mg daily maintenance doses of IV over 0.5 hours 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 to < 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 remdesivir as a treatment option during the pandemic.