Population Pharmacokinetic Analysis of Datopotamab Deruxtecan (Dato‐ <scp>DXd</scp> ), a <scp>TROP2</scp> ‐Directed Antibody‐Drug Conjugate, in Patients With Advanced Solid Tumors

ABSTRACT Datopotamab deruxtecan (Dato‐DXd) is a trophoblast cell surface antigen 2 (TROP2)‐directed antibody‐drug conjugate (ADC) developed for the treatment of advanced or metastatic solid tumors. Dato‐DXd demonstrated promising antitumor activity and a manageable safety profile in the first‐in‐human Phase 1 study TROPION‐PanTumor01. The present work established population pharmacokinetic models for Dato‐DXd and DXd in patients with advanced solid tumors, using data from three clinical studies. The final Dato‐DXd model was a two‐compartment model with both linear (CL linDatoDXd ) and nonlinear elimination. CL linDatoDXd was the major elimination pathway for Dato‐DXd doses ≥ 4 mg/kg, whereas nonlinear clearance was necessary to capture the concentration‐dependent clearance at lower doses. Body weight was added as a mechanistic covariate with a fixed allometric exponent of 0.75 (estimated value: 0.80) on clearance and estimated exponents on volumes of distribution. The final model for DXd was a one‐compartment model with linear clearance (CL DXd ). The release of DXd was equal to the total elimination rate of Dato‐DXd and was found to be time‐dependent within and between cycles, as previously observed for other ADCs. For a typical 66 kg male patient, CL linDatoDXd was 0.386 L/day, central volume of distribution V cDatoDXd was 3.06 L, CL DXd was 2.66 L/day, and V cDXd was 25.1 L. Covariate analysis identified body weight as the most influential covariate on Dato‐DXd and DXd exposure. These findings support the weight‐based dosing strategy and indicate no dose adjustments are warranted based on the covariates evaluated.