請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57086
標題: | 在腎移植病人Everolimus對Tacrolimus藥動學的影響 – 藥動學研究之建立與先期數據 Effect of Everolimus on the Pharmacokinetics of Tacrolimus in Renal Transplant Patients – Establishment of a Pharmacokinetic Study and the Preliminary Data |
作者: | Chan-Chan Si 施珍珍 |
指導教授: | 林慧玲(Fe-Lin Lin Wu) |
共同指導教授: | 蔡孟昆(Meng-Kun Tsai) |
關鍵字: | tacrolimus,everolimus,mycophenolate mofetil,腎移植,藥品動態學,藥品交互作用,免疫抑制劑, tacrolimus,everolimus,mycophenolate mofetil,kidney transplant,pharmacokinetics,drug-drug interaction,immunosuppressants, |
出版年 : | 2014 |
學位: | 碩士 |
摘要: | 背景:
腎移植後常合併多重免疫抑制劑,通常包括calcineurin inhibitors (CNIs: cyclosporine或tacrolimus)、mammalian target of rapamycin (mTOR) inhibitors (如everolimus)、antimetabolites (如mycophenolate mofetil,MMF) 和類固醇。由於CNIs和mTOR inhibitors都是cytochrome P (CYP) 3A和P-glycoprotein (P-gp) 的受質;CNIs和mTOR inhibitors還會抑制CYP3A4,cyclosproine更是很強的P-gp抑制劑,所以當它們併用時可能會互相競爭和抑制這些代謝途徑。臨床上使用含有everolimus的治療方案時,各藥品的藥品動態學 (pharmacokinetics,PK,簡稱藥動學) 是否會改變,臨床療效是否會受影響,仍有待進一步評估。已知MMF和tacrolimus併用時,對tacrolimus的PK影響很少,未達統計上差異,故可以MMF做為對照來探討everolimus對tacrolimus的PK的影響。 目的: 1. 藉由tacrolimus和everolimus的藥動學研究,建立探討藥品交互作用的藥動學研究標準作業流程及模式; 2. 在新腎臟移植的病人,藉由everolimus/tacrolimus/corticosteroids跟MMF/ tacrolimus/corticosteroids兩個治療方案的比較初步了解免疫抑制劑everolimus對tacrolimus藥動學的影響。 方法: 本研究為一前瞻性、隨機分配、開放性、平行比較之藥動學研究,自2014年4月開始在臺大醫院的一般外科病房進行。納入初次接受腎臟移植的台灣人,病人年齡必須在20-65歲,而且胺基轉化酶 (aminotransferase) 的數值必須在正常值上限的兩倍以內。研究排除條件包括:懷孕、結核病、B型肝炎或C型肝炎帶原、人類免疫缺乏病毒 (human immunodeficiency virus,HIV) 反應呈陽性、再移植或多重器官移植、有類風濕關節炎病史以及在試驗期間使用會增加或抑制CYP3A4或P-gp活性的藥品。在取得納入病人之受試者同意書後,隨機分成everolimus/tacrolimus/corticosteroids跟MMF/tacrolimus/corticosteroids兩組。 兩組病人之corticosteroid與tacrolimus療程劑量均遵守醫院標準療程, tacrolimus 0.1- 0.15 mg/kg/day自移植後第1天 (POD1) 開始早晚8時服用,標的谷濃度 (Ctrough) 為8 - 12 ng/mL。Everolimus/tacrolimus/corticosteroids組的病人另自POD1開始早晚8時固定服用everolimus 1 mg。MMF/tacrolimus/ corticosteroids組則以早晚8時服用MMF 10 - 15 mg/kg代替everolimus。當tacrolimus與everolimus血中濃度達到穩定狀態後,分別在給藥前、給藥後1、2、3、5、8小時抽血,利用WinNonlin的non-compartmental analysis得到tacrolimus、everolimus的藥動學參數,以探討everolimus對tacrolimus藥動學的影響。 記錄建立此藥動學研究從文獻蒐集、倫委會申請到案例結案所有過程,將需要的研究記錄表格建檔,彙整後建立標準流程與模式。 結果與討論: 在臨床上發現可能的藥品交互作用問題後,須先進行文獻探討。了解這些問題在臨床上的重要性。回顧各個藥品已知的藥動學資料和藥理機轉,了解藥品特性,思考是否有藥品交互作用的可能或造成交互作用的相關機轉,由此建立假說,決定對照組及受試者的選擇與分組、計算所需受試者人數、檢體與決定取樣時間點、檢體的處理、了解藥品檢驗方法及線性範圍、資料收集、藥動學參數的計算方式、統計分析方法、病人衛教資料等,而且都要在符合研究倫理的大前提下進行。備齊研究計畫書、受試者同意書後,向倫委會提出申請,並登錄於http://clinicaltrials.gov/網頁。 初期研究共納入5位病人。發現病人tacrolimus血中濃度不一定能在移植後第8到第10天到達穩定狀態,所以變更研究架構圖及受試者同意書,更詳細說明是當藥品到達穩定狀態後抽血測定藥動學,預計約移植後第8到10天。另外,抽血時間點也由原本的服藥前及服藥後1、2、3、5、8小時,需要修改為服藥前及服藥後1、2、3、5、8、12小時,因為由目前已納入的病人藥動學推測,服藥後12小時 (晚上8時) 的藥品血中濃度可能比服藥前 (早上8時) 的藥品血中濃度低,甚至有病人服藥後8小時的藥品血中濃度已經比服藥前的低;新增抽血時間點服藥後12小時,可有更多資訊進行分析,且不須使用外推方式計算8到12小時血中濃度-時間曲線下面積 (AUC8-12)。 受試者的共病 (例如糖尿病)、鈣離子通道抑制劑、不良反應等,可能影響藥品藥動學的因子,應考量在兩組間是否有差異。相關性可能存在於tacrolimus和everolimus各自的藥動學參數之間、tacrolimus與everolimus的藥動學之間、腎功能的恢復與藥品藥動學之間,這些都值得進一步探討。 結論: 本研究藉由tacrolimus和everolimus的藥動學研究,建立探討藥品交互作用的前瞻性、隨機分配、開放性、平行比較之藥動學研究標準作業流程及模式。研究於實際納入受試者後,應儘量在不影響研究的可信度和嚴謹性下根據實際情況進行變更、修改。由初步資料可以進一步思考有哪些病人的狀況要注意、值得多花心思的趨勢、可能存在的相關性等。 Background: Multidrug immunosuppression regimens are used after renal transplantation. These regimens generally include individual drugs from two or three of the following classes: calcineurin inhibitors (CNIs: cyclosporine or tacrolimus), mammalian target of rapamycin (mTOR) inhibitor (e.g., everolimus), antimetabolites (e.g., mycophenolate mofetil, MMF) and corticosteroids. CNIs and mTOR inhibitors are substrates for cytochrome P (CYP) 3A and P-glycoprotein (P-gp); in addition, CNIs and mTOR inhibitors are inhibitors of CYP3A4. Cyclosporine is also a potent inhibitor of P-gp. Therefore, concomitant administration of those drugs may alter their serum levels. It remains to be evaluated whether the pharmacokinetics or clinical efficacy of tacrolimus be affected when a regimen contain both everolimus and tacrolimus. MMF has no effect on pharmacokinetics of tacrolimus; therefore, MMF can be used as a control to understand the effects of everolimus on the pharmacokinetics of tacrolimus in kidney transplant patients. Purposes: 1. To establish a standard procedure for a pharmacokinetic study to investigate drug-drug interaction of tacrolimus and everolimus; 2. To have a preliminary analysis for the effects of everolimus on the pharmacokinetics of tacrolimus in de novo Taiwanese kidney transplant patients. Methods: This is a prospective, randomized, open-label, parallel-grouped pharmacokinetic study in general surgical ward at National Taiwan University Hospital starts from April 2014. Patients who undergo first kidney transplantation at the age of 20 to 65 years old, and have an aminotransferase level within 2 times of the upper normal limit will be included. The exclusion criteria are pregnancy, TB, HBV or HCV carrier, human immunodeficiency virus (HIV) positive, re-transplant, multi-organ transplant, rheumatoid arthritis history, use of CYP 3A4 or P-gp inhibitor or inducer during the study period. After signing the informed consent, patients will be randomly assigned to triple therapy with everolimus or MMF in combination with tacrolimus and corticosteroids. The use of corticosteroids and tacrolimus will follow the standard protocol in the hospital. Tacrolimus 0.1 to 0.15 mg/kg/day po q12h will be started from post-operation day (POD) 1, with a target trough concentration (Ctrough) of 8 to 12 ng/mL. In everolimus/tacrolimus/corticosteroids group, everolimus 1 mg po q12h will be started from POD1. In MMF/tacrolimus/corticosteroids group, MMF 10-15 mg/kg po q12h will be used instead of everolimus. The whole blood sample will be collected before dosing and at 1, 2, 3, 5, and 8 hours after the tacrolimus and everolimus dose is administrated when steady state being achieved. WinNonlin non-compartmental analysis will be used to calculate pharmacokinetic parameters of tacrolimus and everolimus in order to understand the effects of everolimus on the pharmacokinetics of tacrolimus. All the procedures involved in the establishment of the pharmacokinetic study will be recored to set up the standard operating procedure (SOP). Results and discussions: When a potential drug-drug interaction is suspected, a literature review should be done first. In order to understand the potential of drug-drug interaction or the potential mechanisms of the drug-drug interaction, the pharmacokinetics, pharmacological mechanism, and properties of those drugs should be reviewed. After that, it is able to establish the hypothesis, determine the control group and grouping of the subjects, calculate sample size of the study, decide the sample volume and sampling time, understand the analytical methods and limit, collect data, calculate pharmacokinetic parameters, select the statistical methods, prepare patient education information, etc. Make sure that all the processes be compliant with research ethics, then submit the study proposal and informed consent to the Research Ethic Committee, and login on the public website http://clinicaltrial.gov/. There were 5 patients in the preliminary analysis. We found that the steady state of tacrolimus might not be attained on POD8 to POD10, and the sampling time in flow chart and informed consent were revised to be more flexible. In addition, the whole blood sample will also be collected at 12 hours after the tacrolimus and everolimus dose is administrated, because the Ctrough in the morning (8 a.m.) might not be the same Ctrough as in the evening (8 p.m). In addition, this may make the estimation of area under the concentration-time curve between 8 to 12 hours (AUC8-12) more accurate. Factors that may affect the pharmacokinetics, such as, comorbidity (e.g., diabetes mellitus), the use of calcium channel blockers, adverse events, should be considered. Correlation may present between the pharmacokinetic parameters of tacrolimus and/or everolimus, and the recovery of renal function. Conclusion: This study established a prospective, randomized, open-label, parallel-grouped pharmacokinetic study. If amendment was necessary after patients’ inclusion, it should be made without affect the reliability of study. Preliminary data showed that we should be cautions of some patients’ conditions that may affect pharmacokinetics; some trends and correlations might present. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57086 |
全文授權: | 有償授權 |
顯示於系所單位: | 臨床藥學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-103-1.pdf 目前未授權公開取用 | 2.5 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。