Effects of pharmacokinetics-related genetic polymorphisms on the side effect profile of afatinib in patients with non-small cell lung cancer

Hayashi, Hideki; Iihara, Hirotoshi; Hirose, Chiemi; Fukuda, Y.; Kitahora, Mika; Kaito, Daizo; Yanase, Komei; Endo, Junki; Ohno, Yasushi; Suzuki, Akio; Sugiyama, Tadashi

doi:10.1016/j.lungcan.2019.05.013

Cited by 22 publications

(18 citation statements)

References 33 publications

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“…Recently, Hayashi et al . reported that genetic polymorphisms related to afatinib had influence on the pharmacokinetics in the early phase and were correlated with the severity of diarrhea 23 . Second, we did not investigate the effect of meals.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

Nakao

Kobuchi

Marutani

et al. 2019

Sci Rep

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To investigate the exposure–safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5–1, 2–3, 8–12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8. Plasma afatinib concentrations were determined using high-performance liquid chromatography. Data was analyzed following the population approach and using the software Phoenix® NLMETM Version 7.0 software (Certara USA, Inc., Princeton, NJ, USA). From 34 patients, a total of 354 afatinib plasma concentration values were available for the population PK analysis. Significant covariates in the population PK model included aspartate aminotransferase and creatinine clearance on CL/F, and age and body mass index on V/F. Results of simulation based on final PK model indicated that hepatic impairment had a significant effect on afatinib levels in plasma after multiple dosing. Afatinib trough plasma concentrations on day 8 were higher in patients with adverse events of grade 3 or higher. The population PK analysis showed that hepatic impairment affected afatinib PK parameters and contributed to the high inter-patient variability and high plasma concentrations of afatinib following multiple treatments.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

Nakao

Kobuchi

Marutani

et al. 2019

Sci Rep

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“…To date, higher afatinib plasma concentrations have been reported to be associated with the severity of diarrhea [14][15][16][17][18]. Therefore, the analysis of plasma concentrations of afatinib may enable the avoidance of diarrhea onset.…”

Section: Introductionmentioning

confidence: 99%

Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer

Yokota

Sato

Sakamoto

et al. 2021

Biology

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We evaluated the area under the plasma concentration–time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C0 and AUC0–24 of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0–1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC0–24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan–Meier analysis based on these cut-off AUC0–24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0–24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0–24 (r2 = 0.840); however, a significant correlation between the AUC0–24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0–24. Therefore, afatinib C0 should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.

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“…This result differs from existing findings of the effect of gene polymorphisms on afatinib. Hayashi et al (9) reported that the afatinib plasma concentration was higher and diarrhoea was more severe in patients carrying the A allele of ABCG2 C421A. However, in this study, ABCB1 G2677T(A) was not investigated.…”

Section: Discussionmentioning

confidence: 66%

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea

Sogawa

Nakashima

Nakamura

et al. 2020

In Vivo

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Background/Aim: Afatinib, a 2 nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. Patients and Methods: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236

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Effects of pharmacokinetics-related genetic polymorphisms on the side effect profile of afatinib in patients with non-small cell lung cancer

Cited by 22 publications

References 33 publications

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea

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