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

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.