Population pharmacokinetics of CP-751,871, a monoclonal antibody against IGF-I receptor, in patients with multiple myeloma or solid tumors

Abstract

2524 Background: CP-751,871, a fully human IgG2 monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), is currently under clinical development for cancer treatment. The aim of the present work was to develop a population model for characterizing the pharmacokinetics (PK) of CP-751,871 in cancer patients. Methods: CP-751,871 concentration-time data were obtained from 34 patients with multiple myeloma and 46 patients with solid tumors, who received escalating doses of CP-751,871 via intravenous infusions in the dose range of 0.1 to 20 mg/kg. Nonlinear mixed effects modeling was conducted using NONMEM to obtain the structural model describing CP-751,871 disposition and the statistic models describing intra- and inter-patient variabilities. Possible covariates contributing to inter-patient PK variability were also explored. Results: A mechanism-based structural PK model with a saturable elimination process best described the disposition of CP-751,871 in cancer patients. For variance models, inter-patient variability in PK disposition parameters was described by an exponential error model, and the residual variability was best described by a log-normal additive residual error model. Body weight was identified as a covariate for the initial distribution volume and the plasma clearance parameters. Age, sex, and albumin or bilirubin concentrations showed no apparent effects on CP-751,871 PK. In addition, there was no apparent difference in PK between multiple myeloma and solid tumor patients. Conclusions: A population PK model was developed to describe the concentration-time profiles of CP-751,871 in cancer patients. The identification of body weight as a significant covariate for plasma clearance validates the appropriateness of body weight-based dosing for CP-751,871. The population PK model can be applied to further explore pharmacokinetic/pharmacodynamic (PK/PD) relationships of CP-751,871 in cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology Pfizer Oncology Pfizer Oncology