大剂量甲氨蝶呤在骨肉瘤患者中的群体药动学研究

发布时间：2018-05-27 23:13

本文选题：骨肉瘤 + 甲氨蝶呤　；参考：《吉林大学》2014年硕士论文

【摘要】：背景与目的：自1972年Jafe开始在临床应用大剂量甲氨喋呤(MTX)化疗方案治疗骨肉瘤以来，已历经数十载，期间对其进行的大量临床研究，使其合理应用日益完善，但因在个体患者中的剂量不同，且用药患者个体存在较大差异，其不良反应仍较严重，偶可致命。当代医学对肿瘤治疗提出了个体化治疗的要求，如何使接受该疗法的骨肉瘤患者从治疗中获益最大、毒性最轻，这需要较以往更新颖、更广泛、更深入的研究方法来加以实现。本文对大剂量甲氨蝶呤的骨肉瘤患者进行了群体药代动力学研究，求得这一群体药动力学参数，并评估患者年龄、性别、体重、谷丙转氨酶(ALT)、谷草转氨酶(AST)、血清肌酐(SCR)等对药动学参数的影响，根据所得模型结合贝叶斯法可对个体患者进行药物浓度预测，为临床个体化治疗提供理论依据。方法：收集2009年1月至2013年12月于吉林大学中日联谊医院血液肿瘤科接受大剂量甲氨蝶呤化疗的58例骨肉瘤患者的相关临床资料，其中女性26例，男性32例。整理患者的甲氨蝶呤血药浓度及固定效应协变量数据(年龄、性别、体重、谷丙转氨酶、谷草转氨酶、血清肌酐)，应用非线性混合效应模型法（NONMEM法）软件——kinetica（version4.4）建立群体药动学模型及计算PPK参数、评估以上各协变量对群体药代动力学模型及参数的影响。结果：大剂量甲氨蝶呤的药代动力学符合二室一级消除模型，大剂量甲氨蝶呤24小时后的代谢过程符合一室一级消除模型，，将不同时间血药浓度经kinetia计算，24小时后的表观容积V0.0597986L，消除速率常数为0.132738。血清肌酐化验值对消除速率常数有相关性，协变量方程为：Kel=0.198236-CREA*0.000665374。结论： 1.本研究应用NONMEM法（Kinetica软件）对大剂量MTX在骨肉瘤患者中的群体药动学进行研究，所得的PPK参数表征了该群体的特性。 2.血清肌酐化验值对消除速率常数（Kel）有相关性，在临床工作中应对肾功能不全患者予以重视，避免或减少毒性反应发生率。 3.Kinectica软件可根据患者的相关临床资料，对MTX血药浓度进行预测，为临床制定个体化治疗方案，减少药物毒性服务。
[Abstract]:Background and purpose: Since 1972, when Jafe began to use high dose methotrexate (MTX) chemotherapy regimen in the treatment of osteosarcoma, it has gone through dozens of years, during which a large number of clinical studies have been carried out, making its rational application more and more perfect, but due to the different doses in individual patients, There were significant differences in individual drug use, and the adverse reactions were still serious and occasionally fatal. Modern medicine has put forward the request of individualized treatment for tumor treatment. How to make the patients with osteosarcoma receiving this therapy benefit the most from the treatment and minimize the toxicity need more novel more extensive and deeper research methods than before. The pharmacokinetics of high dose methotrexate osteosarcoma patients was studied in this paper. The pharmacokinetic parameters were obtained, and the age, sex, body weight of the patients were evaluated. The effects of alanine aminotransferase (alt), aspartate aminotransferase (AST) and serum creatinine (SCR) on pharmacokinetic parameters were studied. According to the model and Bayesian method, the drug concentration of individual patients could be predicted, which could provide theoretical basis for individualized clinical treatment. Methods: The clinical data of 58 patients with osteosarcoma received high dose methotrexate chemotherapy from January 2009 to December 2013 in the Department of Blood Oncology, Sino-Japanese Friendship Hospital of Jilin University were collected, including 26 females and 32 males. To collate the data of MTX serum concentration and fixed effect covariable (age, sex, body weight, transglutaminase, alanine aminotransferase, aspartate aminotransferase). Serum creatinine, using nonlinear mixed effect model (NONMEM) software (kinetica version4.4), to establish a population pharmacokinetic model and calculate the PPK parameters to evaluate the effects of the above covariables on the population pharmacokinetic model and parameters. Results: The pharmacokinetics of high dose methotrexate was in accordance with the two-compartment first-order elimination model, and the metabolic process of high-dose methotrexate 24 hours was consistent with one-compartment first-order elimination model. The apparent volume V0.0597986Lafter 24 hours was calculated by kinetia, and the elimination rate constant was 0.132738L. The serum creatinine test value was correlated with the elimination rate constant, and the covariant equation was 0.198236-CREAA 0.000665374. Conclusion: 1. The pharmacokinetics of high dose MTX in osteosarcoma patients was studied by using NONMEM software. The obtained PPK parameters were used to characterize the characteristics of the population. 2. The serum creatinine test value is related to the elimination of rate constant Kel. it should be paid attention to in clinical work in patients with renal insufficiency to avoid or reduce the incidence of toxic reactions. 3.Kinectica software can predict the blood drug concentration of MTX according to the clinical data of the patients, and make individualized treatment plan for clinic and reduce the drug toxicity service.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R738.1;R969.1

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