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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
Author(s) -
Mittapalli Rajendar K.,
Stodtmann Sven,
Friedel Anna,
Me Rajeev M.,
Bain Earle,
Mensing Sven,
Xiong Hao
Publication year - 2019
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1418
Subject(s) - antibody drug conjugate , temozolomide , pharmacokinetics , antibody , conjugate , population , medicine , epitope , epidermal growth factor receptor , glioblastoma , oncology , drug , cancer research , pharmacology , immunology , monoclonal antibody , cancer , mathematical analysis , mathematics , environmental health
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.