盐酸拓扑替康胶囊和盐酸西莫替尼片T期临床药代动力学、安全性和耐受性研究

发布时间：2018-04-16 09:14

本文选题：盐酸拓扑替康 + 盐酸西莫替尼　；参考：《北京协和医学院》2015年博士论文

【摘要】：本论文以抗肿瘤新药盐酸拓扑替康胶囊和盐酸西莫替尼片为研究对象,建立了快速、灵敏的超高效液相色谱质谱联用(UPLC-MS/MS)法测定人血浆中拓扑替康和西莫替尼的浓度,为上述药物的药代动力学研究以及治疗药物浓度监测提供方法学参考。同时分别探讨了上述药物在晚期肿瘤患者中的药代动力学特征、安全性和耐受性,为指导临床安全、有效和合理用药提供科学依据。主要内容分为两个部分：第一部分：盐酸拓扑替康胶囊Ⅰ期绝对生物利用度、安全性和耐受性研究盐酸拓扑替康是一种水溶性半化学合成喜树碱类抗肿瘤药物,是特异性拓扑异构酶Ⅰ抑制剂。研究表明口服制剂与静脉制剂疗效相当,但血液毒性更低、使用更方便。本研究进行的盐酸拓扑替康胶囊Ⅰ期临床试验是首次在中国人体中进行的绝对生物利用度、安全性和耐受性研究,具体研究内容如下：第一章：建立人血浆中总拓扑替康(内酯型和羧酸盐型)的检测方法。采用UPLC-MS/MS法测定人血浆中总拓扑替康的浓度,并对方法学进行了全部验证。结果显示该方法在0.5～100 ng/mL范围内线性良好,日内、日间精密度范围为1.8%-11.2%,准确度范围为-0.3%-5.7%,提取回收率85%。方法学达到临床药代动力学研究所需检测要求。第二章：建立人血浆中活性药物内酯型拓扑替康的检测方法。采用UPLC-MS/MS法测定人血浆中内酯型拓扑替康的浓度,并对方法学进行了全部验证。结果显示该方法在0.1～50 ng/mL范围内线性良好,日内、日间精密度范围为3.6%-10.7%,准确度范围为-1.6%-5.4%,提取回收率90%。方法学达到临床药代动力学研究所需检测要求。第三章：盐酸拓扑替康胶囊绝对生物利用度、安全性和耐受性研究。采用单中心、非随机、开放和剂量递增设计。共入组11例晚期肿瘤患者,6例患者给予1.5mg/m2静脉和口服给药,5例给予1.5 mg/m2静脉和1.9 mg/m2口服给药。总拓扑替康两个剂量组的绝对生物利用度分别为(41.2±11.8)%和(36.0±14.8)%,内酯型拓扑替康两个剂量组的绝对生物利用度分别为(46.0±15.4)%和(38.3±14.3)%,与文献报道一致,但相同剂量下静脉和口服给药的暴露量要高于白种人。经剂量均一化后分析,ABCG2基因421CA和34GA位点的突变与拓扑替康绝对生物利用度无显著相关性。盐酸拓扑替康胶囊的剂量限制性毒性为骨髓抑制,临床推荐给药剂量为1.5mg/m2,qd,连用5 d,21 d为1个周期。最大耐受剂量(MTD)为1.9 mg/m2,对于年轻、体质好、既往化放疗程度轻的患者,可在该剂量水平进一步研究。第二部分：盐酸西莫替尼片在晚期非小细胞肺癌(NSCLC)患者中单次和连续给药的药代动力学、安全性和耐受性研究盐酸西莫替尼是一种新的小分子表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)。本研究旨在进一步探讨盐酸西莫替尼片在晚期EGFR敏感突变的NSCLC患者中单次和连续给药的药代动力学特征、安全性和耐受性,为Ⅱ期临床推荐给药剂量提供依据,具体研究内容如下：第一章：建立人血浆中西莫替尼的检测方法。采用UPLC-MS/MS法测定人血浆中西莫替尼的浓度,并对方法学进行全部验证。结果显示该方法在1～1000 ng/mL范围内线性良好,日内、日间精密度小于9.3%,准确度范围为-2.5%-2.9%,提取回收率90%,未见明显基质效应。方法学达到临床药代动力学研究所需检测要求。第二章：盐酸西莫替尼片在晚期NSCLC患者中单次和连续给药的临床药代动力学研究。采用单中心、开放、单一剂量递增设计。共获得21例晚期NSCLC患者西莫替尼片单次和连续给药的药代动力学、安全性和耐受性数据。单次口服符合二房室模型,血药浓度-时间曲线呈现双指数函数特征。在200-650 mg剂量范围内,人体暴露量随给药剂量增加而增加,药动学特征符合线性动力学过程。连续口服符合一房室模型,200-650 mg剂量范围内连续给药15天未见明显蓄积,在300-650mg剂量间,暴露量随给药剂量不成比例增加,存在吸收饱和,人体药动学特征为非线性动力学过程。西莫替尼在200-650 mg剂量范围内,2次/日,连续口服给药对EGFR敏感突变的NSCLC患者治疗有效,主要药物相关不良反应为皮疹、瘙痒、腹泻以及白细胞减少,耐受性良好,未达到MTD。
[Abstract]:This paper takes Topotecan Hydrochloride Capsules and Xi Mo hydrochloride in anti-tumor drug imatinib tablets as the research object, to establish a rapid, sensitive ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for the determination of topological concentration in human plasma topotecan and Xi Mo imatinib, provide methodology reference for the study of drug pharmacokinetics and drug treatment at the same time were discussed. Monitoring the concentration of the drug in patients with advanced cancer in the pharmacokinetics, safety and tolerability, for clinical safety, provide scientific basis for effective and rational use of drugs. The main content is divided into two parts: the first part: Topotecan Hydrochloride Capsules of absolute bioavailability, safety and tolerability study topotecan hydrochloride is a kind of water soluble semi chemical synthesis of camptothecin anticancer drugs is a specific inhibitor of topoisomerase. Studies show that oral preparation and A intravenous formulation of curative effect, but the blood less toxic, more convenient to use. The research of the Topotecan Hydrochloride Capsules phase I clinical trial for the first time in Chinese is absolutely biological in the human body availability, safety and tolerability study, the main research contents are as follows: the first chapter: the establishment of general topology in human plasma (topotecan lactone and carboxylate salt type) detection method. Determination of total topology in human plasma topotecan concentration by UPLC-MS/MS method, and the other law were all verified. The results show that the method in the 0.5 ~ 100 ng/mL good linearity in the range of days, inter day precision is in the range of 1.8%-11.2%, the accuracy of the range of -0.3%-5.7%, studying pharmacokinetics research institute to detect the required clinical medicine extraction recovery 85%. method. The second chapter: the establishment of active drug in human plasma lactone. Detection method for topological Kang in human plasma by UPLC-MS/MS method The lactone topotecan concentrations, and the other law were all verified. The results show that the method in the 0.1 ~ 50 ng/mL good linearity in the range of days, inter day precision is in the range of 3.6%-10.7%, the accuracy of the range of -1.6%-5.4%, learn the pharmacokinetic study required detection meets the requirement of clinical medicine extraction recovery 90%. method. The third chapter: Topotecan Hydrochloride Capsules absolute bioavailability, safety and tolerability study. This is a single center, non randomized, open and dose escalation design. A total of 11 patients with advanced cancer patients, 6 patients were given 1.5mg/m2 intravenous and oral administration, 5 patients were treated with 1.5 mg/m2 intravenous and oral Administration of mg/m2 1.9. Topology for absolute biological healthy two dose groups using respectively (41.2 + 11.8)% and (36 + 14.8)%, lactone for absolute biological topology Kang two dose group use respectively (46 + 15.4)% and (38.3 + 14.3)%, and the Reported, but the same dose of intravenous and oral exposure to drugs is higher than white people. By the analysis of the dose homogeneity, the mutation of ABCG2 gene 421CA and 34GA loci and the absolute bioavailability of topotecan. Topotecan Hydrochloride Capsules has no significant correlation with the dose limiting toxicity was myelosuppression, clinical recommended dose 1.5mg/m2, QD, for 5 d, 21 d for 1 cycles. The maximum tolerated dose (MTD) of 1.9 mg/m2, for the young, good physique, previous radiotherapy in patients with mild, further research in the dose level. The second part: Seamus icotinib hydrochloride tablets in advanced non-small cell lung cancer (NSCLC) in patients with single and continuous pharmacokinetics, safety and tolerability of Seamus icotinib hydrochloride is a kind of new small molecule epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). The purpose of this study was to further investigate the salt Seamus acid imatinib tablets in late EGFR sensitive mutant NSCLC in patients with single and continuous to the pharmacokinetics of drugs, safety and tolerability for phase II clinical recommended dosage provides the basis, the specific contents are as follows: the first chapter: the establishment of human plasma and Mo imatinib test methods. Determination the plasma concentration of imatinib and Mo by UPLC-MS/MS method, and the other law were all verified. The results show that this method has good linear and in the range of 1~1000 ng/mL days, day precision is less than 9.3%, the accuracy is in the range of -2.5%-2.9%, the recovery rate of 90%, no significant matrix effect. Pharmacokinetic study required testing requirements the clinical medicine methodology. The second chapter: Seamus icotinib hydrochloride tablets in patients with advanced NSCLC single and continuous administration of clinical pharmacokinetic studies. The single center, open, single dose escalation design. A total of 21 cases received Seamus erlotinib in patients with advanced NSCLC single and continuous pharmacokinetics, safety and tolerability data. A single oral administration with two compartment model. The blood concentration time curve showing the characteristics of double exponential function. At the dose of 200-650 mg within the scope of human exposure with the dose increase. The pharmacokinetic characteristics with linear dynamics. Continuous Administration conformed to one compartment model, 200-650 mg dose range for medicine for 15 days no significant accumulation in 300-650mg exposure dose, with the dose increasing out of proportion, absorption saturation, dynamic characteristics of nonlinear dynamics process of human drug imatinib at 200-650 mg Seamus. Within the dose, 2 times / day, continuous oral administration of mutation sensitive to EGFR NSCLC patients with effective treatment, related major adverse drug reactions were rash, itching, diarrhea and leukopenia, well tolerated, did not reach MT D.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R969

【参考文献】