Utilizing Pharmacokinetics/pharmacodynamics Modeling to Simultaneously Examine Free CCL2, Total CCL2 and Carlumab (CNTO 888) Concentration Time Data

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.