RESUMEN
This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple-dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed-effects modeling approach. A two-compartment model with parallel Michaelis-Menten and time-decreasing linear clearance adequately described the data, the latter being related to post-treatment response. With respect to bias in exposure metrics, the simplified time-varying linear clearance (CL) model was the best alternative. Time-variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady-state was crucial for unbiased estimation of Michaelis-Menten elimination in case of the reference (parallel Michaelis-Menten and time-varying linear CL) model.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Antineoplásicos Inmunológicos/farmacocinética , Terapia Biológica/métodos , Cetuximab/farmacocinética , Neoplasias Colorrectales/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/secundario , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Humanos , Cinética , Modelos Lineales , Masculino , Oncología Médica/estadística & datos numéricos , Persona de Mediana Edad , Modelos Biológicos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Dinámicas no LinealesRESUMEN
The purpose of this research was to investigate the effectiveness of epidermal growth factor receptor (EGFR) targeted micelles loaded with IR-780 (Cetuximab/IR-780/micelles) for generating tumor targeting, multimodal images, and photothermal therapy (PTT). We initially studied the cellular uptake of these micelles using the HCT-116 and SW-620 cell lines. HCT-116 (high expression of EGFR) and SW-620 (low expression of EGFR) cell lines were used to examine biodistribution and antitumor effects of Cetuximab/IR-780/micelles. Time-lapse near-IR fluorescence (NIRF) images also indicated the highest IR-780 accumulation from Cetuximab/IR-780/micelles in HCT-116 tumors (p<0.05). HCT-116 tumors in tumor-bearing mice exhibited significantly higher accumulations of Cetuximab/IR-780/111In-micelles than SW-620 tumors in Micro-SPECT/CT imaging and biodistribution studies (p<0.05). Dual-radioisotope Nano-SPECT/CT imaging of Cetuximab/131I-IR-780/111In-micelles demonstrated simultaneous high accumulation of both IR-780 and micelles in HCT-116 tumors, but not in SW-620 tumors. Regarding antitumor effects, following the Cetuximab/IR-780/micelles with PPT on day 6, all HCT-116 tumor-bearing mice were cured. In contrast, SW-620 tumors relapsed at 13days after treatment. In summary, we expect that the Cetuximab/IR-780/micelles could enhance the antitumor effects by PTT in EGFR overexpression colorectal cancers through effective drug delivery nanoparticles.