Depatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate (ADC) designed for the treatment of tumors expressing epidermal growth factor receptor (EGFR), consisting of a veneered "humanized" recombinant IgG1κ antibody that has binding properties specific to a unique epitope of human EGFR with noncleavable maleimido-caproyl linkers each attached to a potent antimitotic cytotoxin, monomethyl auristatin F. We aimed to describe the development and comparison of 2 population pharmacokinetic modeling approaches. Data from 2 phase 1 studies enrolling patients with glioblastoma multiforme or advanced solid tumors were included in the analysis. Patients in these studies received doses of depatux-m ranging from 0.5 to 4.0 mg/kg as monotherapy, in combination with temozolomide, or radiation plus temozolomide depending on the study and/or arm. First, an integrated ADC model to simultaneously describe the concentration-time data for ADC, total antibody, and cys-mafodotin was built using a 2-compartment model for ADC for each drug-to-antibody ratio. Then, 3 individual models were developed for ADC, total antibody, and cys-mafodotin separately using 2-compartment models for ADC and total antibody and a 1-compartment model for cys-mafodotin. Visual predictive checks suggested accurate model fitting across a range of concentrations. The analysis showed that both an integrated complex ADC model and the individual models that have shorter computational time would result in similar outcomes.