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Trastuzumab Rezetecan (SHR-A1811) is an antibody-drug conjugate (ADC) targeting the human epidermal growth factor receptor 2 (HER2). It features a novel enzyme-cleavable linker and delivers the topoisomerase I inhibitor payload, rezetecan, with a drug-to-antibody ratio of approximately 6.0. Its population pharmacokinetics (PopPK) were characterized using a nonlinear mixed-effects model based on data from 645 patients with HER2-expressing or HER2-mutated advanced solid tumors with 18,671 samples across three phase 1 trials. A two-analyte PopPK model was developed to describe the intact ADC and released payload. The intact ADC followed a two-compartment model with linear elimination, while the payload rezetecan was best described by a one-compartment model with first-order release and linear elimination. Stepwise covariate modeling identified several baseline factors-body weight, tumor size, albumin, aspartate aminotransferase, age, and cancer type-as statistically significant parameters-covariates' relationships. However, their effects on the AUC of both intact ADC and payload were limited (< 20% change). No clinically relevant impacts were observed for race, sex, formulation, or renal/hepatic function on ADC or payload exposure. In conclusion, the developed PopPK model adequately characterizes the pharmacokinetics of Trastuzumab Rezetecan and its released payload. Based on the covariate analysis, no dose adjustments are warranted for the studied patient population. This model can further support dose selection in future clinical trials through exposure-response analyses.