Population Pharmacokinetic and Exposure‐Efficacy Analysis of Baloxavir Marboxil for Influenza Treatment and Post‐Exposure Prophylaxis in Children

Baloxavir acid (baloxavir), the active metabolite of the prodrug baloxavir marboxil, is a selective inhibitor of the influenza virus cap-dependent endonuclease. The population pharmacokinetic (popPK) profile of baloxavir in adults/adolescents has been described previously. To characterize the PK of baloxavir in patients aged ≥1 year, a popPK model was developed using data from 1,795 patients across six studies, including miniSTONE-2 (NCT03629184) in which children aged 1 to <12 years received a bodyweight-based single oral dose of baloxavir marboxil (2 mg/kg, <20 kg; 40 mg, ≥20 kg) for treatment of influenza. The final popPK model was a 2-compartment model with first-order absorption and elimination processes and an absorption lag time; the most influential covariates affecting baloxavir exposure were bodyweight and race (Asian versus non-Asian). Pediatric-to-adult exposure matching for PK parameters relevant for treatment and post-exposure prophylaxis (PEP) indications were used to support pediatric label extensions. Adequate exposure matching was demonstrated between non-Asian pediatric patients using the miniSTONE-2 dose and non-Asian adult patients. After dosing optimization, predicted baloxavir exposures in Asian pediatric patients using the miniSTONE-2 dose were similar to exposures in Asian adults. To bridge PEP efficacy data from the BLOCKSTONE study in Japanese pediatric patients (JapicCTI-184,180) to non-Asian patients aged ≥1 year, an exposure-matching approach between Japanese pediatric patients receiving the lower BLOCKSTONE dose and non-Asian pediatric patients receiving the miniSTONE-2 dose was employed. Together, these observations indicate that the recommended miniSTONE-2 dosing regimen is likely to be efficacious for treatment and PEP in children aged 1-<12 years, regardless of race.