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

Autor: Mo G; Eli Lilly and Company, Indianapolis, IN, USA. gary.mo@lilly.com., Baldwin JR; Eli Lilly and Company, Indianapolis, IN, USA., Luffer-Atlas D; Eli Lilly and Company, Indianapolis, IN, USA., Ilaria RL Jr; Eli Lilly and Company, Indianapolis, IN, USA., Conti I; Eli Lilly and Company, Indianapolis, IN, USA., Heathman M; Eli Lilly and Company, Indianapolis, IN, USA., Cronier DM; Eli Lilly and Company, Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2018 Mar; Vol. 57 (3), pp. 355-365.
DOI: 10.1007/s40262-017-0562-0
Abstrakt: 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.
Databáze: MEDLINE
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