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Modeling restoration of gefitinib efficacy by co‐administration of MET inhibitors in an EGFR inhibitor‐resistant NSCLC xenograft model: A tumor‐in‐host DEB‐based approach
- Source :
- CPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 11, Pp 1396-1411 (2021), CPT: Pharmacometrics & Systems Pharmacology
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB‐based tumor‐in‐host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.
- Subjects :
- Drug
Lung Neoplasms
media_common.quotation_subject
Population
Context (language use)
RM1-950
Article
Mice
Gefitinib
In vivo
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Medicine
Animals
Humans
Pharmacology (medical)
Epidermal growth factor receptor
education
media_common
EGFR inhibitors
education.field_of_study
biology
business.industry
Research
Articles
Xenograft Model Antitumor Assays
respiratory tract diseases
ErbB Receptors
Apoptosis
Drug Resistance, Neoplasm
Modeling and Simulation
Cancer research
biology.protein
Heterografts
Therapeutics. Pharmacology
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 21638306
- Volume :
- 10
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- CPT: Pharmacometrics & Systems Pharmacology
- Accession number :
- edsair.doi.dedup.....4ae5ef7bcf535ef823e23d83bfa972be