PKPD modeling of acquired resistance to anti-cancer drug treatment

Journal of Pharmacokinetics and Pharmacodynamics
Miro J EigenmannAntje-Christine Walz

Abstract

Non-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen. Two semi-mechanistic models were fitted to tumor growth inhibition profiles during and after treatment with erlotinib or gefitinib. The base model proposes that as a result of drug treatment, tumor cells stop proliferating and undergo several stages of damage before they eventually die. The acquired resistance model adds a resistance term to the base model which assumes that resistant cells are emerging from the pool of damaged tumor cells. As a result, tumor cells sensitive to drug treatment will either die or be converted to a drug resistant cell population which is proliferating at a slower growth rate as compared to the sensitive cells. The observed tumor growth profiles were better ...Continue Reading

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Citations

Sep 13, 2019·The AAPS Journal·Pascal SchulthessPiet H van der Graaf
Jul 29, 2018·Cancer Chemotherapy and Pharmacology·Emma C MartinJames W T Yates
Mar 23, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Bharti PanjwaniVijay Mohan

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Methods Mentioned

BETA
xenografts
xenograft

Software Mentioned

Berkeley
Monolix
Lixoft
Madonna

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