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

Abstract

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.

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

“…25 For example, the active plasma concentration of cetuximab in a mouse xenograft model was fairly comparable with those observed in patients. 26 A mechanism-based model could add additional values for translational purpose. Here we described our first effort, an empirical approach, to inform clinical dose selection.…”

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

“…Because of the variable growth rate of the implanted PDX tumors, these studies were performed with an accrual design with data presented as a Kaplan-Meier plot. A 10 mg/kg dose of cetuximab was selected as the comparator since the exposures achieved with this dose would be expected to exceed those achievable in patients (21). In contrast, ABT-806 was assessed at doses of both 10 and 40 mg/kg (dosed three times a week for 2 weeks) because reduced normal tissue binding of ABT-806 compared with cetuximab has been demonstrated thereby allowing higher tolerated doses in patients.…”

Prediction of Active Drug Plasma Concentrations Achieved in Cancer Patients by Pharmacodynamic Biomarkers Identified from the Geo Human Colon Carcinoma Xenograft Model

“…In particular, the tyrosine residue 1068 within the COOH terminus of EGFR becomes autophosphorylated upon activation of EGFR kinase by its natural ligand, whereas the phosphorylated tyrosine 1068, pY1068, plays an essential role in subsequent receptor internalization of EGFR and activation of the MAPK signaling pathway (21,22). Furthermore, we have conducted an in vivo efficacy study to define the efficacious dose range of cetuximab in Geo human colon tumor xenografts grown in nude mice (23). Therefore, the current study was designed to evaluate (a) the phosphorylation status of tyrosine 1068, phospho-EGFR[pY1068], in Geo tumor xenografts in vivo; (b) whether the inhibition of the tumoral phospho-EGFR[pY1068] correlates with the inhibition of EGFR signaling as well as with the antiproliferative effects by cetuximab at efficacious doses; (c) whether the levels of phospho-EGFR/phospho-MAPK could serve as surrogate biomarkers to assess EGFR inhibition by cetuximab.…”