Journal
CLINICAL PHARMACOKINETICS
Volume 57, Issue 3, Pages 355-365Publisher
ADIS INT LTD
DOI: 10.1007/s40262-017-0562-0
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Funding
- Eli Lilly and Company, USA
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Background and Objectives Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-alpha (PDGFR alpha). In a randomized phase II study, olaratumab plus doxorubicin met its pre-defined 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 (R). 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.
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