title: Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.
abstract: 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.
authors.affiliation: PK/PD Core Facility, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Fetterly
authors.forename: Urvi
authors.initials: U
authors.lastname: Aras
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Meholick
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Shobha
authors.initials: S
authors.lastname: Seetharam
authors.forename: Thomas
authors.initials: T
authors.lastname: McIntosh
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Shahneen K
authors.initials: SK
authors.lastname: Sandhu
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000080908:Broadly Neutralizing Antibodies; D018932:Chemokine CCL2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D000080908:Broadly Neutralizing Antibodies; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C581643:carlumab
keywords: PK/PD modeling; cytokine; soluble ligand