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- Title
Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.
- Authors
Fetterly, Gerald J.; Aras, Urvi; Meholick, Patricia D.; Takimoto, Chris; Seetharam, Shobha; McIntosh, Thomas; de Bono, Johann S.; Sandhu, Shahneen K.; Tolcher, Anthony; Davis, Hugh M.; Zhou, Honghui; Puchalski, Thomas A.
- 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.
- Subjects
CLINICAL trials; COMPUTER simulation; INFLAMMATORY mediators; MATHEMATICAL statistics; MONOCLONAL antibodies; TUMORS; PARAMETERS (Statistics); DATA analysis software; STATISTICAL models; DESCRIPTIVE statistics; PHARMACODYNAMICS
- Publication
Journal of Clinical Pharmacology, 2013, Vol 53, Issue 10, p1020
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.140