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

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 T max for the 3 age groups compared to adults. The model was also applied to guide the dosing strategy for 1 st 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.