Clinical Pharmacology & Drug Safety and Metabolism Department, Science & Data Technology Division, R&D, AstraZeneca K.K., Osaka, Japan.
Statistics Group, Science & Data Technology Division, R&D, AstraZeneca K.K., Osaka, Japan.
Cancer Chemother Pharmacol. 2019 May;83(5):849-858. doi: 10.1007/s00280-019-03788-4. Epub 2019 Feb 14.
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.
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.
In the population pharmacokinetic analysis for gefitinib, α-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.
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.
本前瞻性、多中心、大规模队列研究（NCT00252759）纳入了接受吉非替尼治疗的非小细胞肺癌日本患者，旨在确定并量化此类患者发生间质性肺病（ILD）的风险因素，并对其进行定量分析。本研究报告了吉非替尼暴露与 ILD 发生之间的相关性。
共纳入 336 例患者的 1891 个吉非替尼血药浓度，这些浓度分别在首次给药后、稳态时及 ILD 发生时进行测量。采用非线性混合效应模型，研究人口统计学和病理生理学因素对药代动力学的影响。通过比较ILD 发生组和未发生组患者的吉非替尼暴露情况，探讨与吉非替尼诱导的 ILD 相关的风险因素。还对 ILD 发展和正常状态下的个体内暴露情况进行了比较。
在吉非替尼的群体药代动力学分析中，α-酸性糖蛋白（AGP）、年龄、体重和细胞色素 P450 3A4 诱导剂的合并使用是口服清除率（CL/F）的显著协变量。AGP 和体重也是影响分布容积的因素。ILD 发生时的 CL/F 明显低于正常状态时。与未发生 ILD 的患者相比，发生 ILD 的患者吉非替尼的暴露量更高；然而，这些差异无统计学意义。另一方面，在同一患者中，ILD 发生时的暴露量明显高于正常状态时的暴露量。
在 ILD 发生时观察到吉非替尼暴露量显著升高，提示 CL/F 降低可能与 ILD 诱导的 AGP 升高有关。吉非替尼暴露量增加不太可能是ILD 的有力预测指标，也不需要进行剂量调整。
