An Integrated Population Pharmacokinetic Model Versus Individual Models of Depatuxizumab Mafodotin, an Anti‐EGFR Antibody Drug Conjugate, in Patients With Solid Tumors Likely to Overexpress EGFR

Abstract 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.