Utilizing mechanistic PK/PD modeling to simultaneously examine free CCL2, total CCL2, and CNTO 888 serum concentration time data.

Abstract

3029 Background: The chemokine (C-C motif) CCL2 promotes angiogenesis, tumor proliferation, migration, and metastasis. CNTO 888 is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize the time course of CNTO 888, free CCL2, and the CNTO 888-CCL2 complex in the serum. Comprehensive PK/PD modeling of oncology biologics targeting soluble ligands have been rare to date. The goal of the analysis was to predict a dose that will maximally affect CCL2 signaling in the serum and utilize that dose for the clinical development of CNTO 888. Methods: PK and PD data from 21 cancer patients with refractory tumors were examined. CNTO 888 dose levels examined were 0.3, 1, 3, 10 and 15 mg/kg. 3 subjects were treated at each dose level for dose levels < 3 mg/kg and 6 subjects each for the 10 and 15 mg/kg dose levels. All dose levels tested were well tolerated with no dose limiting toxicities. CNTO 888, free CCL2, and CNTO 888-CCL2 complex concentrations in serum were determined following the first and fourth dose. PK/PD modeling was conducted using population-based methods. Results: A mechanistic PK/PD model simultaneously described the temporal relationships among serum concentrations of CNTO 888, free CCL2, and the CNTO 888-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and are consistent with shifting free CCL2, which is rapidly cleared in the absence of CNTO 888 to the form bound to CNTO 888 which is cleared much slower. Free CCL2 declined rapidly after the end of the infusion and returned to baseline concentration within 7 days. Mean predicted half-lives of CNTO 888 and the CCL2-CNTO 888 complex were both 2.4 days and only 1 hour for free CCL2. The mean (%SEM) dissociation constant (KD) was 2.4 nM (72%). Conclusions: A mechanistic PK/PD model was developed that simultaneously describes CNTO 888, free CCL2 and the CNTO 888-CCL2 complex concentration-time data in serum. Model parameter estimates are physiologically plausible. This PK/PD model has the potential to predict clinically relevant changes in free CCL2 and the CNTO 888-CCL2 complex. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Centocor Ortho Biotech Centocor Ortho Biotech Centocor Ortho Biotech