Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 
(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 trastuzumab deruxtecan and 
released drug (topoisomerase I inhibitor) in patients with HER2-positive breast 
cancer or other solid tumor malignancies. This analysis includes pooled data 
from five clinical studies with 639 patients. Trastuzumab deruxtecan doses 
ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab 
deruxtecan and released drug were analyzed using a sequential two-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 trastuzumab deruxtecan and released drug. A 
two-compartment model with linear elimination best described PK profiles of 
intact trastuzumab deruxtecan, while a one-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) resulted in < 20% change in steady-state area under the 
concentration-time curve of trastuzumab deruxtecan 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 trastuzumab deruxtecan or released drug. 
Overall, results suggest that no dose adjustment based on tested covariates or 
in specific patient populations is warranted.