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.

Population pharmacokinetics of belantamab mafodotin, a BCMA‐targeting agent in patients with relapsed/refractory multiple myeloma

“…The PopPK analysis of belamaf ADC, total mAb and cys-mcMMAF concentrations from DREAMM-1 and DREAMM-2 provides a valuable assessment of covariates that impact exposure. The PopPK models characterized the PK of ADC, total mAb and cys-mcMMAF well, described by linear, two-compartment models, consistent with ADC and mAb PK models reported elsewhere 15 , with time-varying CL for ADC and time-varying DAR for cys-mcMMAF. 10, 16,17 PK parameter estimates were in the range of those described for other mAbs in patients with malignancies, including the findings of decreasing CL over time as well as the maximum decrease and time to 50% decrease.…”

“…The PopPK analysis of belamaf ADC, total mAb, and cys‐mcMMAF concentrations from DREAMM‐1 and DREAMM‐2 provides a valuable assessment of covariates that impact exposure. The PopPK models characterized the PK of ADC, total mAb, and cys‐mcMMAF well‐described by linear, two‐compartment models, consistent with ADC and mAb PK models reported elsewhere, 15 with time‐varying CL for ADC and time‐varying DAR for cys‐mcMMAF. 10 , 16 , 17 …”

“…The deconjugation rate constant (Kdec) in the total mAb model was estimated to be 0.059, which is similar to what was reported for depatux‐m (0.0539/day), an ADC with the same linker and payload. 15 …”

“…The deconjugation rate constant (Kdec) in the total mAb model was estimated to be 0.059, which is similar to what was reported for depatux-m (0.0539/day), an ADC with the same linker and payload. 15 Limitations of this PopPK modeling analysis include the small number of patients receiving lower doses of belamaf (and this was only in one study), unanswered questions around the between-study and low-dose effects, and the relatively low number of measurable concentrations available at later timepoints for cys-mcMMAF. However, the models had considerable validity and stability, as determined by GOF, NPDE, and VPC plots, and bootstrapping methods.…”

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

“…MMAF acts as a microtubule disruptor with an average DAR of approximately 4. 116 The design of this ADC is pivotal because of the selectivity profile of the antibody and the expression of the epitope region of EGFR. This epitope is predominantly accessible on tumor cells with EGFRvIII (EGFRde2−7) deletion mutation or EGFR gene amplification with activated wild-type EGFR.…”