Introduction Accurate human pharmacokinetic (PK) prediction for antibody-drug conjugates (ADCs) remains a pivotal challenge in early discovery and preclinical stages. Wild-type (WT) mouse models poorly predict human PK due to species-specific FcRn interactions. While hFcRn transgenic models improve mAb PK prediction, their value for complex ADCs requires further validation. This study evaluates hFcRn and HSA/hFcRn transgenic mice using marketed ADCs to establish their role in translational DMPK assessment. Methods Four ADCs (T-DXd, T-DM1, SG, EV) were administered intravenously (10 mg/kg) to C57BL/6 WT, hFcRn, and HSA/hFcRn mice. Serial blood samples were collected over 28 days. Total antibody and ADC concentrations were measured by ELISA, free payloads by LC-MS/MS. PK parameters were derived via non-compartmental analysis. Results WT mice consistently overestimated ADC half-lives, while hFcRn transgenic models showed human-relevant values. HSA/hFcRn mouse half-lives correlated strongly with human (r²=0.95, p<0.05) and NHP (r²=0.98, p<0.01). Please find the comparison of PK parameters in the table 1. Furthermore, the platform successfully differentiated the stability characteristics between ADCs with stable (T-DXd) and more labile (EV) linkers, providing insights into ADC structure complexity and PK relationships. Conclusion This study demonstrates that hFcRn transgenic mouse model accurately recapitulates human-relevant PK profiles that directly address a major limitation of conventional WT mouse models. The implementation of this platform enables more reliable human PK predictions and informs FIH trial design, and also provides a strategic approach to de-risking ADC development through data-driven candidate selection, reducing early discovery and late-stage dependency on NHP studies, and accelerating the translation of promising ADC therapeutics into clinical evaluation.