Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer

Toshio Kawata, Mitsuo Higashimori, Yohji Itoh, Helen Tomkinson, Martin G. Johnson, Weifeng Tang, Fredrik Nyberg, Haiyi Jiang, Yusuke Tanigawara

Research output: Contribution to journalArticle

Abstract

Purpose: A prospective, multicenter, large-scale cohort with a nested case–control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD. Methods: A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states. Results: In the population pharmacokinetic analysis for gefitinib, α 1 -acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients. Conclusions: Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.

Original languageEnglish (US)
Pages (from-to)849-858
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume83
Issue number5
DOIs
StatePublished - May 1 2019

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Pulmonary diseases
Interstitial Lung Diseases
Non-Small Cell Lung Carcinoma
Cells
Glycoproteins
Pharmacokinetics
gefitinib
Acids
Body Weight
Cytochrome P-450 CYP3A

Keywords

  • Exposure-safety
  • Gefitinib
  • Interstitial lung disease
  • Population pharmacokinetics
  • α -Acid glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer. / Kawata, Toshio; Higashimori, Mitsuo; Itoh, Yohji; Tomkinson, Helen; Johnson, Martin G.; Tang, Weifeng; Nyberg, Fredrik; Jiang, Haiyi; Tanigawara, Yusuke.

In: Cancer chemotherapy and pharmacology, Vol. 83, No. 5, 01.05.2019, p. 849-858.

Research output: Contribution to journalArticle

Kawata, Toshio ; Higashimori, Mitsuo ; Itoh, Yohji ; Tomkinson, Helen ; Johnson, Martin G. ; Tang, Weifeng ; Nyberg, Fredrik ; Jiang, Haiyi ; Tanigawara, Yusuke. / Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer. In: Cancer chemotherapy and pharmacology. 2019 ; Vol. 83, No. 5. pp. 849-858.
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abstract = "Purpose: A prospective, multicenter, large-scale cohort with a nested case–control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD. Methods: A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states. Results: In the population pharmacokinetic analysis for gefitinib, α 1 -acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients. Conclusions: Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.",
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T1 - Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer

AU - Kawata, Toshio

AU - Higashimori, Mitsuo

AU - Itoh, Yohji

AU - Tomkinson, Helen

AU - Johnson, Martin G.

AU - Tang, Weifeng

AU - Nyberg, Fredrik

AU - Jiang, Haiyi

AU - Tanigawara, Yusuke

PY - 2019/5/1

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N2 - Purpose: A prospective, multicenter, large-scale cohort with a nested case–control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD. Methods: A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states. Results: In the population pharmacokinetic analysis for gefitinib, α 1 -acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients. Conclusions: Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.

AB - Purpose: A prospective, multicenter, large-scale cohort with a nested case–control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD. Methods: A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states. Results: In the population pharmacokinetic analysis for gefitinib, α 1 -acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients. Conclusions: Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.

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KW - Interstitial lung disease

KW - Population pharmacokinetics

KW - α -Acid glycoprotein

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