艾维替尼在一组中国晚期非小细胞肺癌病人体内单多次给药代谢产物的药代动力学研究

doi:10.12092/j.issn.1009-2501.2018.10.010

中国临床药理学与治疗学 ›› 2018, Vol. 23 ›› Issue (10): 1147-1152.doi: 10.12092/j.issn.1009-2501.2018.10.010

艾维替尼在一组中国晚期非小细胞肺癌病人体内单多次给药代谢产物的药代动力学研究

王璐¹，郑昕²，王维聪²，赵洪云³，马宇翔³，张力³，胡蓓²，江骥²

¹南京医科大学第一附属医院I期临床试验研究室，南京 210029，江苏；²中国医学科学院，北京协和医院，临床药理研究中心，北京 100032；³中山大学附属肿瘤医院，肿瘤防治中心，广州 510060，广东

收稿日期:2018-09-21 修回日期:2018-09-30 出版日期:2018-10-26 发布日期:2018-10-25
通讯作者: 江骥，男，博士，教授，博士生导师，研究方向：新药I期临床研究。 Tel: 025-69158354 E-mail：13601169983@139.com
作者简介:王璐，女，博士，助理研究员，研究方向：新药I期临床研究。 Tel: 025-68307377 E-mail: wanglu233@foxmail.com
基金资助:
国家自然科学基金青年基金(81503164)；十二五重大新药创制重大专项（2013ZX09401003）

Pharmacokinetics of the metabolites of abivertinib in Chinese patients with advanced NSCLC in a single and multiple dose group

WANG Lu¹, ZHENG Xin², WANG Weicong², ZHAO Hongyun³, MA Yuxiang³, ZHANG Li³, HU Pei², JIANG Ji²

¹Phase 1 Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; ²Clinical Pharmacology Research Center, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 10032, China; ³Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China

Received:2018-09-21 Revised:2018-09-30 Online:2018-10-26 Published:2018-10-25

摘要/Abstract

摘要：

目的: 评价中国晚期非小细胞肺癌患者单多次口服马来酸艾维替尼胶囊，体内代谢产物的药代动力学特征。方法: 7例中国晚期非小细胞肺癌患者单次口服350 mg马来酸艾维替尼胶囊；清洗期后其中3例受试者患者继续350 mg QD连续给药28 d，4例继续175 mg BID连续给药28 d。用高效液相色谱-串联质谱联用(LC-MS/MS)方法测定给药后不同时间艾维替尼5个代谢产物的血药浓度，并用WinNonlin 6.4软件计算主要药代动力学参数。结果: 5个代谢产物中，半胱氨酸结合产物MII-2血浆暴露量最高，占原药的血浆暴露量的3.32%～5.57%。N-去甲基产物M1占原药的血浆暴露量的2.14%～4.24%，单氧化产物M2占原药的血浆暴露量的0.56%～1.00%，酰胺水解产物M4和乙酰半胱氨酸结合产物MII-1暴露量较低，其中MII-1绝大多数样本在血浆中浓度低于定量下限0.1 ng/mL。结论: 监测的5个代谢产物血浆暴露量均未超过原药血浆暴露量的10%。

关键词: 艾维替尼, 代谢产物, 药代动力学, 表皮生长因子受体酪氨酸激酶抑制剂, 液相-质谱联用

Abstract:

AIM: To evaluate the pharmacokinetics of the metabolites of abivertinib in Chinese patients with advanced nonsmall-cell lung cancer (NSCLC) after single and multiple dose of abivertinib maleate capsules. METHODS: Seven Chinese patients with advanced NSCLC were administered a single oral dose of 350 mg of abivertinib maleate capsule. After a washout period, three of them were administered 350 mg of abivertinib QD for 28 days, four were administered 175 mg of abivertinib twice a day for 28 days. The plasma concentrations of five metabolites of abivertinib were assayed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated with WinNonlin ver. 6.4. RESULTS: Among these five metabolites, the exposure of MII-2, a cysteine conjugate, was the highest, which was 3.32%-5.57% of the exposure of the parent drug. The exposures of M1 (N-demethylation) and M2 (N-oxidation) were 2.14%-4.24% and 0.56%-1.00% of the exposure of the parent drug, respectively. The exposures of M4 (N-dealkylation) and MII-1 (acetylcysteine conjugate) were low, most of the concentrations of MII-1 were blow the lower limit of quantitation (0.1 ng/mL). CONCLUSION: The exposures of the five metabolites monitored were no more than 10% of the exposure of the parent drug.

Key words: abivertinib, metabolite, pharmacokinetics, EGFR-TKI, liquid chromatography-tandem mass spectrometry

中图分类号:

王璐，郑昕，王维聪，赵洪云，马宇翔，张力，胡蓓，江骥. 艾维替尼在一组中国晚期非小细胞肺癌病人体内单多次给药代谢产物的药代动力学研究[J]. 中国临床药理学与治疗学, 2018, 23(10): 1147-1152.

WANG Lu, ZHENG Xin, WANG Weicong, ZHAO Hongyun, MA Yuxiang, ZHANG Li, HU Pei, JIANG Ji. Pharmacokinetics of the metabolites of abivertinib in Chinese patients with advanced NSCLC in a single and multiple dose group[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(10): 1147-1152.

参考文献

［1］Haghgoo SM, Allameh A, Mortaz E,et al. Pharmacogenomics and targeted therapy of cancer: Focusing on non-small cell lung cancer［J］. Eur J Pharmacol, 2015, 754:82-91.
［2］Siegel RL, Miller KD, Jemal A. Cancer statistics 2016［J］. CA Cancer J Clin, 2016, 66(1):7-30.
［3］GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013［J］. Lancet, 2015, 385(9963):117-171.
［4］产翠翠, 田静, 金艺凤. 非小细胞肺癌靶向治疗药物的研究进展［J］. 中国临床药理学与治疗学, 2016, 21(3):354-360.
［5］Jorge SE, Kobayashi SS, Costa DB. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data［J］. Braz J Med Biol Res, 2014, 47(11):929-939.
［6］郭磊, 李爱洁, 王键玮,等.盐酸埃克替尼治疗晚期肺腺癌的回顾性研究［J］.中国药物应用与监测,2015, 12(2):69-72.
［7］Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with nonsmall- cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial［J］. Lancet Oncol, 2009, 11(2):121-128.
［8］Zhou C, Wu YL, Chen G, et al, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study［J］. Lancet Oncol, 2011, 12(8):735-742.
［9］Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain［J］. PLoS Med, 2005, 2(3):e73.
［10］Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP［J］. Proc Natl Acad Sci USA, 2008, 105(6):2070-2075.
［11］Kobayashi S, Boggon TJ, Dayaram T, et al.EGFR mutation and resistance of non-small-cell lung cancer to Gefitinib［J］. N Engl J Med, 2005, 352:786-792.
［12］Denis MG, Vallée A, Théoleyre S. EGFR T790M resistance mutation in non small-cell lung carcinoma［J］. Clin Chim Acta, 2015, 444:81-85.
［13］吕巧妹, 金春英, 张红娟, 等. 化疗序贯EGFR-TKI治疗EGFR-TKI获得性耐药晚期非小细胞肺癌患者的临床观察［J］. 疑难病杂志, 2016, 15(3):280-283+291.
［14］Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models［J］. Oncogene,2008, 27(34): 4702-4711.
［15］Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial［J］. Lancet Oncol, 2012, 13(5):528-538.
［16］Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer［J］. Cancer Discov, 2014, 4(9):1046-1061.
［17］Finlay MR, Anderton M, Ashton S, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor［J］. J Med Chem, 2014, 57(20):8249-8267.
［18］Jnne PA, Yang JC, Kim DW, et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer［J］. N Engl J Med, 2015, 372 (18): 1689-1699.
［19］Costa DB, Kobayashi SS. Whacking a mole-cule: clinical activity and mechanisms of resistance to third generation EGFR inhibitors in EGFR mutated lung cancers with EGFR-T790M［J］. Transl Lung Cancer Res, 2015, 4(6):809-815.
［20］Xu X, Mao L,Xu W,et al. AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients［J］. Mol Cancer Ther, 2016, 15(11):2586-2597.
［21］Yan X,Zhou Y,Huang S. Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma［J］. J Cancer Res Clin Oncol, 2018, 144(4):697-706.
［22］Ma Y,Zheng X,Zhao H, et al. First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non-Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance［J］. J Thorac Oncol,2018, 13(7):968-977.
［23］Wang L, Zheng X, Wang W,et al.An LC-MS/MS method for quantification of AC0010, a novel mutant-selective epidermal growth factor receptor (EGFR) inhibitor, and its metabolites in human plasma and the application to a pharmacokinetic study［J］. J Pharm Biomed Anal, 2017, 141:9-18.

[1]	何雪茹, 李颖, 马银玲, 付裕豪, 荀雪姣, 董占军. 索拉非尼和达格列净在大鼠体中药代动力学相互作用研究[J]. 中国临床药理学与治疗学, 2023, 28(5): 498-507.
[2]	李梦雪, 何杰, 余霞霞, 胡琳璘, 邵华. 利妥昔单抗群体药代动力学研究进展[J]. 中国临床药理学与治疗学, 2023, 28(4): 468-474.
[3]	周佳婷, 张玄, 谢子兰, 李智. 肠道菌群与左旋甲状腺素：相互影响与临床意义[J]. 中国临床药理学与治疗学, 2023, 28(11): 1307-1314.
[4]	吴莉莉, 梁至, 黄思咏, 王妍. 肾功能亢进对感染性心内膜炎患者万古霉素药动学的影响及有效性与安全性研究[J]. 中国临床药理学与治疗学, 2023, 28(10): 1139-1145.
[5]	徐涛, 朱素燕, 邱相君, 徐萍. 肾功能不全患者人群中替考拉宁群体药代动力学模型的建立与验证[J]. 中国临床药理学与治疗学, 2022, 27(9): 977-983.
[6]	马申, 刘玉硕, 唐辉, 陈文斌, 高聆. 改善非酒精性脂肪性肝病药物的药代动力学及其临床意义[J]. 中国临床药理学与治疗学, 2022, 27(8): 908-918.
[7]	戴静怡, 王晶晶, 张菁, 郁继诚, 李南洋, 黄志伟. 吸入性甲氧氟烷的临床应用及研究进展[J]. 中国临床药理学与治疗学, 2022, 27(7): 808-813.
[8]	潘淑, 吴义金, 张洒洒, 王启海, 罗婷婷, 殷勤. 基于OAT3介导的MTX治疗佐剂诱导性关节炎大鼠的药动学研究[J]. 中国临床药理学与治疗学, 2022, 27(5): 516-525.
[9]	吴娟, 王志强, 周仁鹏, 杨晶晶, 秦慧玲, 张茜, 鲁超, 胡伟. 甲苯磺酸索拉非尼片在中国健康受试者的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(3): 281-286.
[10]	史革鑫, 崇锐, 贺坤, 吴海棠, 周宇, 顿中军, 温清, 张继国, 张荣. 吗替麦考酚酯胶囊在中国健康男性受试者空腹及餐后状态下的完全重复交叉设计的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(11): 1255-1263.
[11]	郭璐, 钟振东, 韩奕岑, 石毅, 杨勇, 边原, 刘晓姝, 张静, 郎琴, 钟甜. 不同给药方式在大鼠内对利巴韦林的药代动力学和组织分布的影响[J]. 中国临床药理学与治疗学, 2022, 27(1): 25-32.
[12]	贾元威, 沈杰, 储冀汝, 张翠锋, 谢海棠, 杨斌, 李相鸿, 郑丹丹, 赵静惠. 豆腐果苷及其代谢产物时辰药动学研究[J]. 中国临床药理学与治疗学, 2021, 26(9): 986-994.
[13]	林良沫, 符祥俊, 钟莉莉, 王和芳, 吴琼诗, 肖坚. 中性粒细胞缺乏患者万古霉素群体药代动力学模型的建立[J]. 中国临床药理学与治疗学, 2021, 26(9): 1014-1022.
[14]	付淑军, 黄芳华, 顾景凯, 吴伟, 孙涛, 王庆利. 纳米药物非临床药代动力学的研究策略及关注要点[J]. 中国临床药理学与治疗学, 2021, 26(8): 842-850.
[15]	徐慧, 杨新宇, 赵哲辉, 王琰. 多糖药物体内代谢及PK/PD关键技术研究的进展与思考[J]. 中国临床药理学与治疗学, 2021, 26(8): 851-862.

艾维替尼在一组中国晚期非小细胞肺癌病人体内单多次给药代谢产物的药代动力学研究

Pharmacokinetics of the metabolites of abivertinib in Chinese patients with advanced NSCLC in a single and multiple dose group

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价