010: Development of a Mechanistic-Physiologically Based Pharmacokinetic Platform Model to Guide Adult & Pediatric Dosing for Bispecific T Cell Engagers through Intravenous & Subcutaneous Administration

Statement of Purpose: Bispecific T cell engagers have revolutionized the therapeutic paradigm for cancer patients and is shifting beyond adults to pediatrics and some modalities shifting from intravenous (IV) to more convenient subcutaneous (SC) dosing across indications from liquid to solid tumors. We have broad clinical development experience of bispecific T cell engagers with 3 generations of molecules under development and the first-to-market approval in this class (BLINCYTO®). Hereby we present the development of a mechanistic-physiologically-based pharmacokinetic (PBPK) platform model for bispecific T cell engagers to predict the PK for adults and pediatric patients through IV and SC administration. The platform model is to guide the adult and pediatric dose design to support clinical development of bispecific T cell engagers.

Description of Methods & Materials: The platform model was developed leveraging preclinical and clinical data based on a full PBPK model framework using commercial platform. Drug elimination was assumed to mainly occur through non-specific catabolism and target-mediated drug disposition (TMDD). TMDD model was incorporated for CD3 as T-cell target and tumor-specific antigen as second target as appropriate. Following the verification of the base model using IV dosing, absorption parameters were included, and model further extended for SC dosing. Adult clinical PK dataset from 8 modalities including 3 generations of bispecific T cell engagers across indications were utilized for model development and validation. The model was further refined to predict pediatric PK in 1 month – less than 2 years, 2 – 11 years and 12 – 17 years old subjects incorporating physiological ontogeny and validated using clinical pediatric PK data following IV dosing. Lastly, model was refined to include the ontogeny influencing the SC absorption for pediatric SC PK prediction.

Data & Results: The adult model was successfully validated for PK prediction following IV and SC dosing for the 8 modalities encompassing 3 generations of bispecific T cell engagers. The C_max and AUC predictions were within 2-fold of the observed data (0.7 – 1.5-fold for C_max and 0.7 – 1.8-fold for AUC). The pediatric model was validated for all the 3 age groups PK prediction following IV dosing, with C_max and AUC predictions within 2-fold of the observed data (0.7 – 1.0-fold for C_max and 0.5 – 1.2-fold for AUC). After refinement to include ontogeny parameters influencing pediatric PK from SC dosing, the model predicted similar bioavailability. However, with incorporation of ontogeny for absorption parameters, a shorter T_max in pediatric patients of the 3 age groups compared to adults was predicted. These model predictions were verified using clinical observed data in the literature of various age groups.

Interpretation, Conclusion or Significance: This work highlights, the first to our knowledge, a PBPK platform model for bispecific T cell engagers in adults and pediatric populations. Pediatric simulations successfully evaluated the impact of ontogeny on the PK of bispecific T cell engagers. The impact of ontogeny changes on exposure in tandem with exposure-response relationships for safety and efficacy can be used to guide dose design for adult and pediatric cancer patients and optimal clinical development for bispecific T cell engagers.

Disclosures: