盐酸埃克替尼临床疗效、不良反应与药代动力学的相关性分析
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摘要
目的：通过观察盐酸埃克替尼在中国非小细胞肺癌(NSCLC)患者中药代动力学特点及其临床疗效、不良反应,分别研究两者之间的相关性,从而加强对新药盐酸埃克替尼的了解,以更好的指导临床治疗。
方法：2007年8月至2009年4月在北京协和医院进行了一项中国非小细胞肺癌患者口服盐酸埃克替尼安全性、耐受性以及药代动力学的Ⅰ期、单中心、开放的研究。本课题对当时入组40名患者的临床资料、临床疗效、不良事件进行记录分析,计算每位患者的单药及连续给药的药代动力学相关数据(如达峰时间Tmax,(?)浓度Cmax,零点时间至无穷大时间点的曲线下面积AUC0-∞,外推的AUC百分比AUCextrap%,表观分布容积Vz/F,口服清除率CL/F,末次可测血药浓度Clast,零点时间至可测定浓度值时间点的曲线下面积AUCo-last等)。结合临床疗效和不良事件发生情况来分析是否与其药代动力学参数存在相关性。
结果：临床疗效方面,本研究中盐酸埃克替尼中位PFS为160天,中位OS为454天,而类似研究中,TRUST研究提示厄洛替尼中位PFS为98天,中位OS233天；管忠震等研究吉非替尼的中位PFS为97天,中位OS300天。INTEREST研究提示吉非替尼中位OS为228天。因此,盐酸埃克替尼在PFS、OS方面优于其他同类产品。评估生活质量量表后发现,口服盐酸埃克替尼后受试者在总健康状况评分上有所改善,并且肺癌特异性子量表评分显著减小(P=0.001),说明肺癌相关临床症状(如咳嗽、咯血等)有显著的改善。症状评分方面,疲倦、恶心呕吐、疼痛、食欲丧失、腹泻等症状评分均有显著减小。特别是疼痛症状的缓解(P=0.042),是肺癌患者重要的预后因子。口服盐酸埃克替尼最常见的不良事件为皮疹,其次为腹泻。严重不良事件主要有肺间质疾病。药代动力学结果显示盐酸埃克替尼易于吸收,消除快。分析临床疗效和药代动力学相关性方面,发现盐酸埃克替尼药物暴露程度(Cmax和AUC)和临床抗肿瘤效果没有显著相关性,可能和样本量较少有关。本研究中受试者口服剂量远小于最大耐受剂量MTD625mg/TID,因此可能在此剂量范围内未显出明显相关性。此外,观察到在吸烟患者中OS与AUC0-last似有相关,不除外吸烟对药物暴露的影响,也不除外EGFR基因突变情况会引起此结果。在分析不良事件发生率及严重程度与药代动力学的相关性时,未发现皮疹、腹泻这两种最常见副作用的发生率、严重程度与药代动力学参数之间有显著相关性。可能与样本量小、发生率少有关,也不能除外与受试者口服剂量远小于最大耐受剂量相关。
Objective:This research was to observe the correlation between pharmacokinetic characteristics and the clinical curative effect of icotinib in treatment for Chinese patients with non-small cell lung cancers (NSCLC).
Methods:A retrospective analysis was made on clinical data of a single center phase Ⅰ open clinical trial of icotinib at Peking Union Medical College Hospital from August2007to April2009. This research reviewed the clinical data, efficacy and pharmacokinetics of40patients in the phase Ⅰ study. Pharmacokinetic datas such as Tmax， Cmax, AUC0-∞, AUCextrap%, Vz/F, CL/F, Clast, Tlast, AUC0-last, etc were analyzed in every single patient with single dosing and continuous dosing. At last, correlation test was validated, to research the correlation between pharmacokinetic characteristics and the clinical curative effect.
Results:In terms of clinical efficacy, Icotinib is better than Erlotinib and Gefitinib in PFS, OS. The median PFS in this research is160days and the median OS is454days.The results of TRUST research show that the median PFS of Erlotinib is98days, and median OS of Erlotinib is233days.The results of INTEREST research show that the median OS of Gefitinib is228days. Zhongzhen Guan etc. found that the median PFS of Gefitinib is97days, and the median OS is300days. Icotinib can improve the quality of life, and can significantly relieve lung cancer related clinical symptoms. The symptoms such as fatigue, nausea and vomiting, pain, loss of appetite, diarrhea are relieved. The reduction of pain is an important prognostic factor of patients with lung cancer. The most common adverse event is skin rashes followed by diarrhea. A main serious adverse event is interstitial lung disease. Pharmacokinetic results show that Icotinib is easily absorbed and the metabolic rate of Icotinib in patients is fast. The results of correlation analysis of the clinical efficacy and pharmacokinetic parameters show that the drug exposure (Cmax and AUC) has no significant correlation with clinical antitumor effect. This conclusion might be related with the small sample size of this study. But in smoking patients, OS seems to have correlation with AUC0-last.It is possible that smoking can affect the drug exposure. This research doesn't find any correlation between the incidence and severity of adverse events with pharmacokinetic parameters.
方法：2007年8月至2009年4月在北京协和医院进行了一项中国非小细胞肺癌患者口服盐酸埃克替尼安全性、耐受性以及药代动力学的Ⅰ期、单中心、开放的研究。本课题对当时入组40名患者的临床资料、临床疗效、不良事件进行记录分析,计算每位患者的单药及连续给药的药代动力学相关数据(如达峰时间Tmax,(?)浓度Cmax,零点时间至无穷大时间点的曲线下面积AUC0-∞,外推的AUC百分比AUCextrap%,表观分布容积Vz/F,口服清除率CL/F,末次可测血药浓度Clast,零点时间至可测定浓度值时间点的曲线下面积AUCo-last等)。结合临床疗效和不良事件发生情况来分析是否与其药代动力学参数存在相关性。
结果：临床疗效方面,本研究中盐酸埃克替尼中位PFS为160天,中位OS为454天,而类似研究中,TRUST研究提示厄洛替尼中位PFS为98天,中位OS233天；管忠震等研究吉非替尼的中位PFS为97天,中位OS300天。INTEREST研究提示吉非替尼中位OS为228天。因此,盐酸埃克替尼在PFS、OS方面优于其他同类产品。评估生活质量量表后发现,口服盐酸埃克替尼后受试者在总健康状况评分上有所改善,并且肺癌特异性子量表评分显著减小(P=0.001),说明肺癌相关临床症状(如咳嗽、咯血等)有显著的改善。症状评分方面,疲倦、恶心呕吐、疼痛、食欲丧失、腹泻等症状评分均有显著减小。特别是疼痛症状的缓解(P=0.042),是肺癌患者重要的预后因子。口服盐酸埃克替尼最常见的不良事件为皮疹,其次为腹泻。严重不良事件主要有肺间质疾病。药代动力学结果显示盐酸埃克替尼易于吸收,消除快。分析临床疗效和药代动力学相关性方面,发现盐酸埃克替尼药物暴露程度(Cmax和AUC)和临床抗肿瘤效果没有显著相关性,可能和样本量较少有关。本研究中受试者口服剂量远小于最大耐受剂量MTD625mg/TID,因此可能在此剂量范围内未显出明显相关性。此外,观察到在吸烟患者中OS与AUC0-last似有相关,不除外吸烟对药物暴露的影响,也不除外EGFR基因突变情况会引起此结果。在分析不良事件发生率及严重程度与药代动力学的相关性时,未发现皮疹、腹泻这两种最常见副作用的发生率、严重程度与药代动力学参数之间有显著相关性。可能与样本量小、发生率少有关,也不能除外与受试者口服剂量远小于最大耐受剂量相关。
Objective:This research was to observe the correlation between pharmacokinetic characteristics and the clinical curative effect of icotinib in treatment for Chinese patients with non-small cell lung cancers (NSCLC).
Methods:A retrospective analysis was made on clinical data of a single center phase Ⅰ open clinical trial of icotinib at Peking Union Medical College Hospital from August2007to April2009. This research reviewed the clinical data, efficacy and pharmacokinetics of40patients in the phase Ⅰ study. Pharmacokinetic datas such as Tmax， Cmax, AUC0-∞, AUCextrap%, Vz/F, CL/F, Clast, Tlast, AUC0-last, etc were analyzed in every single patient with single dosing and continuous dosing. At last, correlation test was validated, to research the correlation between pharmacokinetic characteristics and the clinical curative effect.
Results:In terms of clinical efficacy, Icotinib is better than Erlotinib and Gefitinib in PFS, OS. The median PFS in this research is160days and the median OS is454days.The results of TRUST research show that the median PFS of Erlotinib is98days, and median OS of Erlotinib is233days.The results of INTEREST research show that the median OS of Gefitinib is228days. Zhongzhen Guan etc. found that the median PFS of Gefitinib is97days, and the median OS is300days. Icotinib can improve the quality of life, and can significantly relieve lung cancer related clinical symptoms. The symptoms such as fatigue, nausea and vomiting, pain, loss of appetite, diarrhea are relieved. The reduction of pain is an important prognostic factor of patients with lung cancer. The most common adverse event is skin rashes followed by diarrhea. A main serious adverse event is interstitial lung disease. Pharmacokinetic results show that Icotinib is easily absorbed and the metabolic rate of Icotinib in patients is fast. The results of correlation analysis of the clinical efficacy and pharmacokinetic parameters show that the drug exposure (Cmax and AUC) has no significant correlation with clinical antitumor effect. This conclusion might be related with the small sample size of this study. But in smoking patients, OS seems to have correlation with AUC0-last.It is possible that smoking can affect the drug exposure. This research doesn't find any correlation between the incidence and severity of adverse events with pharmacokinetic parameters.
引文
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