Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2-Positive Breast Cancer and Other Solid Tumors.

Trastuzumab deruxtecan (T-DXd; DS-8201) is a HER2-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of T-DXd and released drug (free DXd) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from 5 clinical studies with 639 patients. T-DXd doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of T-DXd and released drug were analyzed using a sequential 2-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of T-DXd and released drug. A 2-compartment model with linear elimination best described PK profiles of intact T-DXd, while a 1-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase [AST]) resulted in < 20% change in steady-state AUC of T-DXd and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact T-DXd or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.