Population Pharmacokinetic Modeling of Brentuximab Vedotin, a CD30-Directed Antibody-Drug Conjugate, and its cytotoxic payload (MMAE) in Patients With Various Hematological Malignancies
Ajit Suri (1), Diane Mould (2), Graham Jang (3), Dirk Huebner (1) and Karthik Venkatakrishnan (1)
(1) Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company (2) Projections Research, Inc (3) Seattle Genetics Inc.
Objectives: To develop population pharmacokinetic models of Brentuximab Vedotin (BV), an antibody-drug conjugate (ADC) and its cytotoxic payload (MMAE) following a 30-minute intravenous infusion of BV administered at 1.8 mg/kg given every 3 weeks.
Methods: The population pharmacokinetics were evaluated (using NONMEM versions 7.2 and 7.3) from several studies including data from 380 patients with various hematological malignancies such as relapsed or refractory (r/r) Hodgkin lymphoma, r/r systemic anaplastic large-cell lymphoma or cutaneous T-Cell Lymphoma.
Results: The model for ADC PK was a linear three-compartment model with zero-order input and first-order elimination. ADC clearance (CL) fell with increasing albumin (ALB); CL and central volume of distribution (Vc) increased with increased body surface area (BSA). The final ADC model included pcALCL tumor type and anti-therapeutic antibody (ATA) status. ATA positivity resulted in increased ADC CL, but overall impact on AUC was minimal (9-12% lower). Higher ADC exposure (approx 35%) in pcALCL patients was observed, but considered relatively modest. The model for MMAE included a link to ADC elimination using the individual parameter estimates from the ADC model to predict the ADC concentrations in the MMAE model. The PK of MMAE was described by a two-compartment model with first-order elimination and formation of MMAE both directly from ADC and through binding of ADC to a hypothetical target. Several patient-specific factors were investigated for their influence on ADC and MMAE PK and the impact of all significant covariates was relatively small. Influence of age, gender and race was not significant in ADC or MMAE models. The final POP PK model was evaluated by Visual Predictive Check method. The simulated concentrations appeared reasonably consistent with the observed concentrations, with no systematic bias. Simulations showed that there is little accumulation of ADC and MMAE exposure with this regimen.
Conclusions: Overall the POP PK models for ADC and MMAE characterized the data well. These analyses provided important support for the proposed dose of BV in the planned sBLA/ MAA filings for CTCL indication.