本文選題：骨肉瘤 + 甲氨蝶呤��； 參考：《吉林大學》2014年碩士論文

【摘要】：背景與目的： 自1972年Jafe開始在臨床應用大劑量甲氨喋呤(MTX)化療方案治療骨肉瘤以來，已歷經(jīng)數(shù)十載，期間對其進行的大量臨床研究，使其合理應用日益完善，但因在個體患者中的劑量不同，且用藥患者個體存在較大差異，其不良反應仍較嚴重，偶可致命。當代醫(yī)學對腫瘤治療提出了個體化治療的要求，如何使接受該療法的骨肉瘤患者從治療中獲益最大、毒性最輕，這需要較以往更新穎、更廣泛、更深入的研究方法來加以實現(xiàn)。本文對大劑量甲氨蝶呤的骨肉瘤患者進行了群體藥代動力學研究，求得這一群體藥動力學參數(shù)，并評估患者年齡、性別、體重、谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)、血清肌酐(SCR)等對藥動學參數(shù)的影響，根據(jù)所得模型結(jié)合貝葉斯法可對個體患者進行藥物濃度預測，為臨床個體化治療提供理論依據(jù)。 方法： 收集2009年1月至2013年12月于吉林大學中日聯(lián)誼醫(yī)院血液腫瘤科接受大劑量甲氨蝶呤化療的58例骨肉瘤患者的相關(guān)臨床資料，其中女性26例，男性32例。整理患者的甲氨蝶呤血藥濃度及固定效應協(xié)變量數(shù)據(jù)(年齡、性別、體重、谷丙轉(zhuǎn)氨酶、谷草轉(zhuǎn)氨酶、血清肌酐)，應用非線性混合效應模型法（NONMEM法）軟件——kinetica（version4.4）建立群體藥動學模型及計算PPK參數(shù)、評估以上各協(xié)變量對群體藥代動力學模型及參數(shù)的影響。 結(jié)果： 大劑量甲氨蝶呤的藥代動力學符合二室一級消除模型，大劑量甲氨蝶呤24小時后的代謝過程符合一室一級消除模型，，將不同時間血藥濃度經(jīng)kinetia計算，24小時后的表觀容積V0.0597986L，消除速率常數(shù)為0.132738。血清肌酐化驗值對消除速率常數(shù)有相關(guān)性，協(xié)變量方程為：Kel=0.198236-CREA*0.000665374。 結(jié)論： 1.本研究應用NONMEM法（Kinetica軟件）對大劑量MTX在骨肉瘤患者中的群體藥動學進行研究，所得的PPK參數(shù)表征了該群體的特性。 2.血清肌酐化驗值對消除速率常數(shù)（Kel）有相關(guān)性，在臨床工作中應對腎功能不全患者予以重視，避免或減少毒性反應發(fā)生率。 3.Kinectica軟件可根據(jù)患者的相關(guān)臨床資料，對MTX血藥濃度進行預測，為臨床制定個體化治療方案，減少藥物毒性服務。
[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.
【學位授予單位】：吉林大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R738.1;R969.1

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