Abstract
PurposeA 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.MethodsA 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.ResultsIn the population pharmacokinetic analysis for gefitinib, α1-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.ConclusionsSignificant 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.
Highlights
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a well-established therapy for the treatment of EGFR-activating mutation-positive non-small-cellAstraZeneca R&D, Gaithersburg, MD, USA 7 Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku‐ku, Tokyo 160‐8582, Japan1 3 Vol.:(0123456789)Cancer Chemotherapy and Pharmacology (2019) 83:849–858 lung cancer (NSCLC) [1]
The population pharmacokinetics of gefitinib were described based on a one-compartment model, after first-order absorption with lag time (Table 2)
According to the estimated parameters, CL/F and volume of distribution (V/F) increased with an increase in body weight, and the exponents of acid glycoprotein (AGP) terms on the CL/F and V/F equations were negative values, suggesting that an increase in AGP induced a decrease in CL/F and V/F
Summary
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a well-established therapy for the treatment of EGFR-activating mutation-positive non-small-cell. The EGFR TKI gefitinib (IRESSA®) was first approved for the treatment of advanced NSCLC in Japan in July 2002. In clinical trials and pre-approval clinical compassionate use, some reports of interstitial lung disease (ILD)-type events were observed. ILD, especially idiopathic interstitial fibrosis, is a known comorbidity in patients with NSCLC and is associated with some lung cancer therapies [6]. Statistical analysis was performed that identified risk factors for ILD occurrence, namely older age, poor World Health Organization (WHO) performance status, smoking history, recent NSCLC diagnosis, reduced lung coverage on computed tomography scan, pre-existing chronic ILD, and concurrent cardiac disease [3]. We report the results from an exposure–response analysis of gefitinib for the occurrence of ILD in Japanese patients with NSCLC, based on population pharmacokinetic and multivariate logistic regression analyses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
