Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft

摘要: Purpose: 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, proven to be effective the treatment advanced cancer. To date, there not study systematically evaluate pharmacokinetics (PK) Cetuximab preclinical model further explore any correlation drug exposure between animal models cancer patients. In present study, we characterized PK nude mice at efficacious dose levels compared optimal active plasma concentration those determined clinical studies. Experimental design: antitumor activity was evaluated using GEO carcinoma xenografts implanted subcutaneously mice. administered ip every 3 days for five total injections (inj) (q3dx5) ranging from 1 mg/inj 0.04 mg/inj. 1.0, 0.25, single bolus iv or administration tumoral bearing xenografts. were quantitated by ELISA assay. Results: demonstrated dose-dependent 0.1, mg/inj, statistically significant delay (in reaching target size gm) 18 (P<0.001), 12.3 (P<0.01), 10 (P<0.01) respectively. A separate employing same schedule showed that equally 0.25 Therefore, can considered within range, while higher appeared model. When given mice, elimination half life (t1/2) 39.6, 37.8, 42.2 h doses respectively, suggesting similar disposition kinetics this range. volume distribution (Vd) ranged 0.062 l/kg 0.070 l/kg, is primarily confined compartment limited peripheral tissue distribution. Clearance (CL) no apparent saturation observed across 1.0 1, maximum (Cmax) 407.6, 66.4, 16.5 μg/ml. area under curve (AUC) 19212.4, 3182.4, 534.5 μg/ml h, average steady state (Css avg) multiple dosing estimated 73.1 as concentration. 2.6 0.53 ng/mg-tumor 112.6 18.3 ng/mg EGFR nearly completely occupied Conclusion: corresponding being patients, i.e. 65–100 significantly lower than current dose. However, range concentrations patients treated regimen. It appears predicts better development antibody drugs.