Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

ABSTRACT

BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM®. RESULTS: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.