Influence of genetic polymorphisms on gefitinib pharmacokinetics and adverse drug reactions in non-small cell lung cancer patients

Prathvi V Shenoy; Gayathri Baburaj; Rama Rao Damerla; Ananth Pai; Sharada Mailankody; Murali Munisamy; Surulivelrajan Mallayasamy; Karthik S Udupa; Jill Kolesar; Mahadev Rao

doi:10.1007/s10555-025-10299-7

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Influence of genetic polymorphisms on gefitinib pharmacokinetics and adverse drug reactions in non-small cell lung cancer patients

Journal article

Open access

Peer reviewed

Influence of genetic polymorphisms on gefitinib pharmacokinetics and adverse drug reactions in non-small cell lung cancer patients

Prathvi V Shenoy, Gayathri Baburaj, Rama Rao Damerla, Ananth Pai, Sharada Mailankody, Murali Munisamy, Surulivelrajan Mallayasamy, Karthik S Udupa, Jill Kolesar and Mahadev Rao

Cancer and metastasis reviews, Vol.44(4), 82

11/06/2025

DOI: 10.1007/s10555-025-10299-7

PMCID: PMC12592279

PMID: 41199076

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Abstract

Gefitinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of non-small cell lung cancer (NSCLC). It is metabolized extensively in the liver by enzymes encoded by CYP3A4, CYP2D6, and CYP3A5 and is the substrate of membrane transporters including ABCB1 and ABCG2. Evidence shows that single-nucleotide polymorphisms (SNPs) in these metabolizing and transporting genes contribute to the inter-individual variability in gefitinib response and development of gefitinib-induced adverse drug reactions (ADRs). This narrative review identifies the existing literature exploring the impact of SNPs on plasma gefitinib concentration and ADRs in patients with NSCLC receiving gefitinib therapy. SNPs were identified in drug-metabolizing enzyme coding genes, including CYP3A4, CYP2D6, CYP3A5, and other CYP homologs, drug transporters including ABCB1, ABCG2, SLCO1B1 and other genes, including UGT1A7 and FOXO3. Current research has not identified any genetic association between specific SNPs in ABCB1, OATP1B1, and UGT1A7 and the pharmacokinetics of gefitinib. Additionally, most of these studies focused on individual SNP associations; however, it may be more important to consider them in combination to better understand their collective impact on gefitinib ADR. Hence, further comprehensive research is essential to examine these genetic variants across different ethnic groups, monitor the drug-drug interactions, and study the phenoconversion to draw definitive conclusions about the pharmacokinetics of gefitinib. This could lead to the development and implementation of a genotyping-based approach for gefitinib dosage optimization in clinical settings.

Antineoplastic Agents - adverse effects

Antineoplastic Agents - pharmacokinetics

Carcinoma, Non-Small-Cell Lung - drug therapy

Carcinoma, Non-Small-Cell Lung - genetics

Drug-Related Side Effects and Adverse Reactions - genetics

Gefitinib - adverse effects

Gefitinib - pharmacokinetics

Humans

Lung Neoplasms - drug therapy

Lung Neoplasms - genetics

Lung Neoplasms - pathology

Polymorphism, Single Nucleotide

Protein Kinase Inhibitors - adverse effects

Protein Kinase Inhibitors - pharmacokinetics

Details

Title: Subtitle: Influence of genetic polymorphisms on gefitinib pharmacokinetics and adverse drug reactions in non-small cell lung cancer patients
Creators: Prathvi V Shenoy - Manipal Academy of Higher Education
Gayathri Baburaj - Manipal Academy of Higher Education
Rama Rao Damerla - Kasturba Medical College, Manipal
Ananth Pai - Manipal Academy of Higher Education
Sharada Mailankody - Kasturba Medical College, Manipal
Murali Munisamy - All India Institute of Medical Sciences Bhopal
Surulivelrajan Mallayasamy - Manipal Academy of Higher Education
Karthik S Udupa - Manipal Academy of Higher Education
Jill Kolesar - University of Iowa
Mahadev Rao - Manipal Academy of Higher Education
Resource Type: Journal article
Publication Details: Cancer and metastasis reviews, Vol.44(4), 82
DOI: 10.1007/s10555-025-10299-7
PMID: 41199076
PMCID: PMC12592279
NLM abbreviation: Cancer Metastasis Rev
ISSN: 0167-7659
eISSN: 1573-7233
Publisher: Springer Nature
Grant note: Manipal Academy of Higher Education, Manipal
Open access funding provided by Manipal Academy of Higher Education, Manipal
Language: English
Date published: 11/06/2025
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics; Obstetrics and Gynecology
Record Identifier: 9985024138402771

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