本文選題：鹽酸拓撲替康 + 鹽酸西莫替尼��； 參考：《北京協(xié)和醫(yī)學院》2015年博士論文

【摘要】：本論文以抗腫瘤新藥鹽酸拓撲替康膠囊和鹽酸西莫替尼片為研究對象,建立了快速、靈敏的超高效液相色譜質(zhì)譜聯(lián)用(UPLC-MS/MS)法測定人血漿中拓撲替康和西莫替尼的濃度,為上述藥物的藥代動力學研究以及治療藥物濃度監(jiān)測提供方法學參考。同時分別探討了上述藥物在晚期腫瘤患者中的藥代動力學特征、安全性和耐受性,為指導臨床安全、有效和合理用藥提供科學依據(jù)。主要內(nèi)容分為兩個部分：第一部分：鹽酸拓撲替康膠囊Ⅰ期絕對生物利用度、安全性和耐受性研究鹽酸拓撲替康是一種水溶性半化學合成喜樹堿類抗腫瘤藥物,是特異性拓撲異構酶Ⅰ抑制劑。研究表明口服制劑與靜脈制劑療效相當,但血液毒性更低、使用更方便。本研究進行的鹽酸拓撲替康膠囊Ⅰ期臨床試驗是首次在中國人體中進行的絕對生物利用度、安全性和耐受性研究,具體研究內(nèi)容如下：第一章：建立人血漿中總拓撲替康(內(nèi)酯型和羧酸鹽型)的檢測方法。采用UPLC-MS/MS法測定人血漿中總拓撲替康的濃度,并對方法學進行了全部驗證。結果顯示該方法在0.5～100 ng/mL范圍內(nèi)線性良好,日內(nèi)、日間精密度范圍為1.8%-11.2%,準確度范圍為-0.3%-5.7%,提取回收率85%。方法學達到臨床藥代動力學研究所需檢測要求。第二章：建立人血漿中活性藥物內(nèi)酯型拓撲替康的檢測方法。采用UPLC-MS/MS法測定人血漿中內(nèi)酯型拓撲替康的濃度,并對方法學進行了全部驗證。結果顯示該方法在0.1～50 ng/mL范圍內(nèi)線性良好,日內(nèi)、日間精密度范圍為3.6%-10.7%,準確度范圍為-1.6%-5.4%,提取回收率90%。方法學達到臨床藥代動力學研究所需檢測要求。第三章：鹽酸拓撲替康膠囊絕對生物利用度、安全性和耐受性研究。采用單中心、非隨機、開放和劑量遞增設計。共入組11例晚期腫瘤患者,6例患者給予1.5mg/m2靜脈和口服給藥,5例給予1.5 mg/m2靜脈和1.9 mg/m2口服給藥�？偼負涮婵祪蓚�劑量組的絕對生物利用度分別為(41.2±11.8)%和(36.0±14.8)%,內(nèi)酯型拓撲替康兩個劑量組的絕對生物利用度分別為(46.0±15.4)%和(38.3±14.3)%,與文獻報道一致,但相同劑量下靜脈和口服給藥的暴露量要高于白種人。經(jīng)劑量均一化后分析,ABCG2基因421CA和34GA位點的突變與拓撲替康絕對生物利用度無顯著相關性。鹽酸拓撲替康膠囊的劑量限制性毒性為骨髓抑制,臨床推薦給藥劑量為1.5mg/m2,qd,連用5 d,21 d為1個周期。最大耐受劑量(MTD)為1.9 mg/m2,對于年輕、體質(zhì)好、既往化放療程度輕的患者,可在該劑量水平進一步研究。第二部分：鹽酸西莫替尼片在晚期非小細胞肺癌(NSCLC)患者中單次和連續(xù)給藥的藥代動力學、安全性和耐受性研究鹽酸西莫替尼是一種新的小分子表皮生長因子受體酪氨酸激酶抑制劑(EGFR-TKI)。本研究旨在進一步探討鹽酸西莫替尼片在晚期EGFR敏感突變的NSCLC患者中單次和連續(xù)給藥的藥代動力學特征、安全性和耐受性,為Ⅱ期臨床推薦給藥劑量提供依據(jù),具體研究內(nèi)容如下：第一章：建立人血漿中西莫替尼的檢測方法。采用UPLC-MS/MS法測定人血漿中西莫替尼的濃度,并對方法學進行全部驗證。結果顯示該方法在1～1000 ng/mL范圍內(nèi)線性良好,日內(nèi)、日間精密度小于9.3%,準確度范圍為-2.5%-2.9%,提取回收率90%,未見明顯基質(zhì)效應。方法學達到臨床藥代動力學研究所需檢測要求。第二章：鹽酸西莫替尼片在晚期NSCLC患者中單次和連續(xù)給藥的臨床藥代動力學研究。采用單中心、開放、單一劑量遞增設計。共獲得21例晚期NSCLC患者西莫替尼片單次和連續(xù)給藥的藥代動力學、安全性和耐受性數(shù)據(jù)。單次口服符合二房室模型,血藥濃度-時間曲線呈現(xiàn)雙指數(shù)函數(shù)特征。在200-650 mg劑量范圍內(nèi),人體暴露量隨給藥劑量增加而增加,藥動學特征符合線性動力學過程。連續(xù)口服符合一房室模型,200-650 mg劑量范圍內(nèi)連續(xù)給藥15天未見明顯蓄積,在300-650mg劑量間,暴露量隨給藥劑量不成比例增加,存在吸收飽和,人體藥動學特征為非線性動力學過程。西莫替尼在200-650 mg劑量范圍內(nèi),2次/日,連續(xù)口服給藥對EGFR敏感突變的NSCLC患者治療有效,主要藥物相關不良反應為皮疹、瘙癢、腹瀉以及白細胞減少,耐受性良好,未達到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.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R969

【參考文獻】

相關期刊論文 前3條

1 孟棄逸;朱允中;張樹才;徐麗艷;劉U，

本文編號：1758242