Background and Objective <p>Patritumab deruxtecan (HER3-DXd, also known as MK-1022) is an antibody–drug conjugate comprising a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload, deruxtecan (DXd), via a tetrapeptide-based cleavable linker. We developed a population pharmacokinetic (PK) model for anti-HER3-ac-DXd (anti-HER3 antibody conjugated DXd) and DXd to characterize their PKs and investigate the impact of preselected covariates.</p> Methods <p>Data were pooled from four phase I/II studies including patients with breast, lung, and colorectal cancer (<i>N</i> = 733) treated with HER3-DXd monotherapy (1.6–8.0 mg/kg intravenously every 3 weeks). An integrated population PK model, established using stepwise methodology, simultaneously described both anti-HER3-ac-DXd and DXd disposition.</p> Results <p>Anti-HER3-ac-DXd PK was described by a two-compartment model with three elimination pathways: linear transient clearance, nonspecific time-dependent clearance, and nonlinear Michaelis–Menten clearance. DXd PK was described by a one-compartment model with two clearance pathways: linear and nonlinear Michaelis–Menten clearance. The formation of DXd was rate limited by all three clearance pathways of anti-HER3-ac-DXd. Moderate hepatic impairment was a significant covariate on DXd but not anti-HER3-ac-DXd exposure. Other prespecified covariates did not have a clinically important impact on exposure to anti-HER3-ac-DXd or DXd.</p> Conclusions <p>The final integrated population PK model characterized the PK of both anti-HER3-ac-DXd and DXd in patients with solid tumors treated with HER3-DXd and supported the selected 5.6 mg/kg Q3W dosing regimen. Consistent with current data, dose adjustment based on the covariates investigated is not warranted.</p>