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Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data
Author(s) -
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.
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.140
Subject(s) - pharmacodynamics , pharmacokinetics , ccl2 , dissociation constant , pharmacology , monoclonal antibody , angiogenesis , in vitro , chemokine , medicine , chemistry , endocrinology , receptor , antibody , immunology , biochemistry
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 (K D ), 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.