Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters

Ma, Yuxiang; Xin, Shuang; Huang, Min; Yang, Yunpeng; Zhu, Chunrong; Zhao, Hongyun; Zhang, Y; Chen, Lingyan; Zhao, Yuanyuan; Li, J; Zhuang, Wei; Zhu, Xia; Zhang, L; Wang, X

doi:10.1038/tpj.2016.31

Cited by 30 publications

(63 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…44 In our previous study, ABCB1 polymorphism was found to be correlated with Gefitinib skin toxicity. 45 We, for the first time, examined the association of ABCB1 rs2235040 CT genotype with periorbital oedema in GIST patients treated with Imatinib, finding it a valuable protective factor in predicting this toxicity.…”

Section: Discussionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

Self Cite

View full text Add to dashboard Cite

Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI = 1.791-27.837, P = 0.005 for EGFR rs10258429 CT +TT vs CC), and 4.809 (95%CI = 1.267-18.431, P = 0.021 for SLC22A1 rs683369 GG+CG vs CC). The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were protective factors to periorbital oedema with OR of 0.313 (95%CI = 0.149-0.656, P = 0.002 for SLC22A5 rs274558 AA+AG vs GG), and 0.253 (95%CI = 0.079-0.805, P = 0.020 for ABCB1 rs2235040 CT vs CC). These results indicated that variants in EGFR, SLC22A1, SLC22A5 and ABCB1 influenced the incidence of Imatinib-induced ophthalmological toxicities, and polymorphism analyses in associated genes might be beneficial to optimize Imatinib treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several studies have evaluated the relationship between the genotype of the metabolizing enzyme/transporter and PKs or toxicity of EGFR TKIs . ABCB1 rs1128 503 or ABCG2 rs2231 142 SNPs were found to be related to increased gefitinib adverse events, such as skin rash and/or diarrhoea .…”

Section: Discussionmentioning

confidence: 99%

A safety, pharmacokinetic, pharmacogenomic and population pharmacokinetic analysis of the third‐generation EGFR TKI, olmutinib (HM61713), after single oral administration in healthy volunteers

Noh

Yoon

Kim

et al. 2019

Basic Clin Pharma Tox

View full text Add to dashboard Cite

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non‐compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter‐individual variability and to evaluate the influence of possible covariates using NONMEM®. Tmax was 2‐3 hour, regardless of race. The mean terminal half‐life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose‐normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single‐nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one‐compartment model with first‐order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100‐300 mg was safe and well tolerated. PK parameters were dose‐proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S‐transferase might be involved in olmutinib metabolism.

show abstract

“…In previous reports regarding gefitinib therapy and ABCG2 C421A, it was unclear whether the polymorphisms were associated with clinical efficacy. Some previous studies showed that gefitinib is associated with a higher frequency of adverse effects in wild-type versus variant-type ABCG2 C421A (35)(36)(37). Meanwhile, Cusatis et al reported that patients with reduced ABCG2 activity due to genetic variants are at increased risk of diarrhea on gefitinib treatment (35).…”

Section: Discussionmentioning

confidence: 99%

Effects of the ABCG2 C421A Polymorphism on Plasma Gefitinib Concentration

Sakamoto

2019

Preprint

View full text Add to dashboard Cite

Background In patients with epidermal growth factor (EGFR) exon 21 L858R mutation-positive non-small cell lung cancer (NSCLC) treated with gefitinib, we found that a lower plasma gefitinib concentration was associated with shorter progression-free survival (PFS). ATP-binding castle protein G2 (ABCG2) is considered to inhibit the activities of certain gefitinib transporters, which affects drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on cell membrane. Previous studies showed that proton pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. Methods A total of 61 patients with advanced EGFR-positive NSCLC were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels, and the area under the curve (AUC) value for 24-hour gefitinib concentration. We also compared these parameters among four groups distinguished according to the presence/absence of the polymorphism and PPI use. Results The mean trough gefitinib level, and the AUC value for 24-hour gefitinib concentration, were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 ± 188.7 vs. 454.5 ± 206.3 ng/mL, P=0.021; AUC: 9,949.9 ± 5,058.9 vs. 13,085.4 ± 5,075.3 ng・h/mL, P=0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 ± 112.6 vs. 340.5 ± 98.3 ng/mL, P=0.033). Conclusions The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentration.

show abstract

Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters

Cited by 30 publications

References 33 publications

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

A safety, pharmacokinetic, pharmacogenomic and population pharmacokinetic analysis of the third‐generation EGFR TKI, olmutinib (HM61713), after single oral administration in healthy volunteers

Effects of the ABCG2 C421A Polymorphism on Plasma Gefitinib Concentration

Contact Info

Product

Resources

About