曲妥珠单抗—美登木素生物碱代谢产物的药代动力学研究

发布时间：2018-06-30 01:14

本文选题：抗体偶联细胞毒素制剂药物(ADC) + T-DM1　；参考：《复旦大学》2014年硕士论文

【摘要】：曲妥珠单抗-美登木素生物碱(T-DM1)是一类抗体偶联细胞毒素制剂药物(Antibody Drug Conjugates ADC),其临床用于人表皮生长因受体-2(HER2)阳性乳腺癌治疗。本文针对它的两种代谢产物DM1-MC C与DM1,综合药代动力学的研究方法和检测手段,通过药物的吸收、分布、代谢、排泄特性(ADME)和药动学参数等方面阐述了它们的药代动力学概况。论文的第一章,综述了HER2阳性乳腺癌治疗药物T-DM1临床前和临床研究概况。回顾了药代动力学与类药性质概念并深入讨论药物在发现阶段的研究思路。此外,巯基化合物在药物递送系统(DDS)有广泛应用,它具有肿瘤细胞的靶向性质在药物设计与开发中得到很大重视。本章基于DM1与DM1-MCC结构特征,讨论并分析了其研究现状与代谢方式为后文中药动学实验方案提供理论依据与参考。在第二章为实验部分,分为(1)分别选择4个种属Balb/c裸鼠、SD大鼠、比格犬与人的血浆考察DM1-MCC与游离DM1血浆稳定性数据；(2)使用MDR1-MDCK细胞株单层膜通透模型研究DM1-MCC渗透性；(3)以多种给药途径静脉注射、腹腔注射、经口灌胃(10% captisol制剂)、经口灌胃(玉米油制剂)给药Balb/c裸鼠；静脉注射、皮下注射(SC)、口服给药比格犬DM1-MCC,采用液质联用技术(LC-MS/MS)同时测定DM1-MCC、游离态DM1与总DM1血药浓度。得到的结果为：(1)血浆稳定性实验显示DM1-MCC于Balb/c裸鼠、SD大鼠血浆半衰期极短分别为t1/2lmin和t1/2=1.5min,而比格犬与人血浆中相对稳定。游离DMl于Balb/c裸鼠、SD大鼠与人血浆有相近清除行为,半衰期分别为t1/2= 13.2min、11.7min和29min；比格犬t1/2=108.5min。(2)MDR1-MDCK单层膜通透性数据表明DM1-MCC有低渗透性与高外排率,各浓度下RE均大于15。(3)Balb/c裸鼠药动学参数显示DM1-MCC有极快的清除率,在所有给药途径中均未测得(LLOQ=1ng/m11。游离DM1在IP给药途径下Tmax=0.25hr, Cmax=24.4ng/ml, t1/2=2hr, AUCiast=18.1 hr·ng/ml。总DM1在1V给药后Cl=16.5L/hr/kg, Vss=11.2L/kg, MRTINF=0.681hr; IP、PO(10% captisol制剂)、PO(玉米油制剂)给药后生物利用度(F)分别为133%、5.43%和19.8%。DM1-MCC分别在比格犬＝和SC中观察到,而更高浓度的游离DMl和总DM1在各给药方式下测得。其中,IV途径游离DM1与总DM1参数分别是Cl=1.05L/hr/kg和0.436L/hr/kg, Vss=0.466和1.35, t1/2=0.576hr和5.67hr, AUCiast=104.2hr·ng/ml和213hr·ng/ml, MRTINF=0.531hr和2.77hr。比格犬SC、PO给药后生物利用度分别为89.1%和45.8%。第三章中我们对研究工作进行汇总并得到结论。含硫酯的DM1-MCC在血浆中容易水解,导致Balb/c裸鼠与比格犬血药浓度维持在较低水平。由DM1-MCC高外排率推测其可能是p-gp泵出底物,此外低溶解度导致其渗透性差。DM1-MCC玉米油制剂相对于10% captisol能够显著提高DMl在Balb/c裸鼠体内的生物利用度。比格犬游离DM1血药浓度普遍高于Balb/c裸鼠表明其可能有更大毒性风险。
[Abstract]:Tratozumab-Madden lignin alkaloid (T-DM1) is a class of Antibody drug conjugate ADCs, which is used in the treatment of human epidermal growth factor receptor 2 (HER2) positive breast cancer. In this paper, the pharmacokinetics of DM1-MC C and DM1, two metabolites of DM1-MC C and DM1, were reviewed in terms of their absorption, distribution, metabolism, excretion characteristics (ADME) and pharmacokinetic parameters. In the first chapter, the preclinical and clinical studies of Her2-positive breast cancer drug T-DM1 are reviewed. The concepts of pharmacokinetics and pharmacokinetic properties were reviewed. In addition, sulfhydryl compounds are widely used in drug delivery system (DDS). Based on the structural characteristics of DM1 and DM1-MCC, this chapter discusses and analyzes the present research status and metabolic patterns of DM1 and DM1-MCC, which provide theoretical basis and reference for the later experimental scheme of Chinese traditional medicine. In the second chapter, the experiment was divided into (1) the plasma stability data of DM1-MCC and free DM1 were investigated in the plasma of four Balb / c nude mice SD rats, Beagle dogs and human plasma, (2) the permeability of DM1-MCC was studied by using MDR1-MDCK cell line monolayer membrane permeability model. (3) Balb / c nude mice were given intravenously, intraperitoneally, orally (10% captisol), and orally (corn oil) by various ways. The plasma concentrations of free DM1 and total DM1 were determined by LC-MS / MS method after subcutaneous injection (SC) and oral administration of DM1-MCC. The results were as follows: (1) the plasma stability test showed that the plasma half-life of DM1-MCC in Balb / c SD rats was very short (t1/2lmin and t 1 / 2) 1.5 mins, and that in Beagle dogs and human plasma was relatively stable. Free DMl in Balb / c nude rat / SD rats was similar to that in human plasma, and the half-life was t _ 1 / 2 = 13.2min ~ 11.7min and 29min, respectively, while in Beagle dog t _ 1 / 2108.5min. (2) the permeability data of MDR1-MDCK monolayer membrane showed that DM1-MCC had low permeability and high efflux rate. (3) the pharmacokinetic parameters of Balb / c nude mice showed that DM1-MCC had an extremely fast clearance rate, which was not detected in all drug delivery pathways (LLOQN 1ng / m11). Free DM1 was treated by IP administration with Tmaxl 0.25hr-1, Cmaxl 24.4ng / ml, T1 / 2ng / ml, AUCiasta 18.1 hr / ng.ml. The bioavailability (F) of total DM1 was 1330.43% and 19.8.DM1-MCC were observed in Beagle dog = and SC, respectively, and the higher concentrations of free DMl and total DM1 were observed in Beagle dog = and SC, respectively. The bioavailability of IPPO (10% captisol preparation) and corn oil preparation (F) was 1.33% and 19.8.DM1-MCC, respectively, in Beagle dog = and SC, while the higher concentration of free DMl and total DM1 were measured under different administration modes. The parameters of free DM1 and total DM1 in IV pathway were ClN 1.05L / hr / kg and 0.436L / hr / kg, VSS 0.466 and 1.35, t1/2=0.576hr and 5.67hrl, AUCiast104.2hr ng/ml and 213hr ng / ml, MRTINF0.531hr and 2.77hr. respectively. The bioavailability was 89. 1% and 45. 8%, respectively. In the third chapter, we summarize the research work and draw a conclusion. DM1-MCC containing sulfur ester was easily hydrolyzed in plasma, which resulted in the low concentration of Balb / c in nude mice and Beagle dogs. The high efflux rate of DM1-MCC suggested that DM1-MCC might be the substrate of p-gp pump. In addition, the low solubility of DM1-MCC cornoil preparation could significantly increase the bioavailability of DML in Balb / c nude mice compared with 10% captisol. The plasma concentration of free DM1 in Beagle dogs was generally higher than that in Balb / c nude mice.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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