Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Nov 2005
Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft.
The epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers including colon and breast, has been strongly associated with tumor progression. Cetuximab, an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody, has been proven to be effective in the treatment of advanced colon cancer. To date, there has not been a study to systematically evaluate the pharmacokinetics (PK) of Cetuximab in a preclinical model and to further explore any correlation of drug exposure between animal models and cancer patients. In the present study, we characterized the PK of Cetuximab in nude mice at efficacious dose levels and further compared the preclinical optimal dose and active plasma drug concentration with those determined in clinical studies. ⋯ In the present study, we compared the preclinical optimal dose and the corresponding active plasma concentration determined in mice with those being observed in cancer patients, i.e. 65-100 microg/ml. The preclinical optimal dose of 0.25 mg/inj was significantly lower than the current clinical dose. However, the active plasma concentration at 0.25 mg/inj is within the range of the active drug concentrations in cancer patients treated with Cetuximab under the current optimal dosing regimen. It appears that the active plasma drug concentration determined in preclinical model predicts better than the optimal preclinical dose for the clinical development of antibody drugs.