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

作　　者：王璐 郑昕 王维聪 赵洪云[3] 马宇翔[3] 张力[3] 胡蓓 江骥 WANG Lu;ZHENG Xin;WANG Weicong;ZHAO Hongyun;MA Yuxiang;ZHANG Li;HU Pei;JIANG Ji(Phase 1Clinical Trial Unit,the First Affiliated Hospital of Nanjing Medical University,Narijing 210029,Jiangsu,China;Clinical Pharmacology Research Center,Peking Union Medical College,Chinese-Academy of Medical Sciences,Beijing 10032,China;Department of Medical Oncology ,Sun Yat-sen University Cancer Center ,Guangzhou510060,Guangdong,China)

机构地区：[1]南京医科大学第一附属医院Ⅰ期临床试验研究室,江苏南京210029 [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,广东广州510060

出　　处：《中国临床药理学与治疗学》2018年第10期1147-1152,共6页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：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)

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/m L。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%。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/m L). CONCLUSION: The exposures of the five metabolites monitored were no more than 10% of the exposure of the parent drug.

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 

分 类 号：R56[医药卫生—呼吸系统] R734[医药卫生—内科学]