A Mechanistic Physiologically‐Based Pharmacokinetic Platform Model to Guide Adult and Pediatric Intravenous and Subcutaneous Dosing for Bispecific T Cell Engagers

Abstract

Bispecific T cell engagers (Bi‐TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi‐TCEs are rapidly evolving from conventional intravenous (IV) to more convenient subcutaneous (SC) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across 3 generations of Bi‐TCE molecules across both liquid and solid tumor indications from IV/SC dosing in adults and pediatric subjects, we developed a mechanistic physiologically‐based pharmacokinetic (PBPK) platform model for Bi‐TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following IV and SC dosing across both liquid and solid tumor space in adults for 8 Bi‐TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PK in 1 month – less than 2 years, 2 – 11 years and 12 – 17 years old subjects following IV dosing. Following SC dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter Tmax for the 3 age groups compared to adults. The model was also applied to guide the dosing strategy for 1st generation of Bi‐TCEs for organ impairment, specifically renal impairment and was able to accurately predict impact of renal impairment on PK for these relatively small‐size Bi‐TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adults and pediatrics across liquid and solid tumor indications from IV/SC dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi‐TCEs.