臺灣博碩士論文加值系統

背景與目的：C型肝炎病毒（hepatitis C virus）感染影響全球數百萬人，對於接受器官移植患者的影響更甚。直接作用抗病毒藥物（direct-acting antiviral agents, DAAs）以組合療程治療C型肝炎感染可達良好成效，其中paritaprevir/ritonavir/ombitasvir/dasabuvir的組合治療基因型第1型C型肝炎之持續性病毒學反應（sustained virologic response, SVR）達成率高且副作用少，但此藥品組合用於器官移植病人須注意藥物交互作用（drug interactions）。Cyclosporine （CsA）為器官移植後重要的免疫抑制劑，由於paritaprevir/ritonavir/ombitasvir/dasabuvir和CsA都經由cytochrome P450（CYP）3A與P-醣蛋白（P-glycoprotein, P-gp）等路徑代謝，併用這兩者可能引起嚴重的藥物交互作用。藥品仿單及文獻建議paritaprevir/ritonavir/ombitasvir/dasabuvir與CsA併用時，CsA的劑量應調降為併用此藥品組合前每日總劑量的五分之一，每天給予一次。但臨床發現此劑量建議並不適合臺灣器官移植病人，且尚無移植病人結束該藥品組合治療後，CsA調整回原劑量頻次之建議。目前也無臺灣器官移植病人使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合的有效性和安全性研究。因此本研究以評估臺灣器官移植病人併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合之下CsA的藥物動力學變化，以及二者併用的有效性和安全性。
方法：本研究利用臺北榮民總醫院電子病歷資料進行回溯性分析，在2017年1月至9月間，納入基因型第1型C型肝炎，接受paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療並使用CsA的肝臟或腎臟移植病人。利用非室性模式（non-compartmental method）計算CsA藥物動力學參數，以非參數疊加法（nonparametric super-positioning）推估併用該藥品組合之下CsA的調整劑量；採用混合效應模型（mixed effect model）評估該藥品組合對CsA的影響與安全性，並以C型肝炎病毒量變化評估藥品組合之有效性。
結果：本研究共納入7位病人，腎移植病人5位，肝移植病人2位。在CsA藥物動力學方面，paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合使用第1天時，CsA的AUC∞/D增加5.18倍，CsA的T1/2由5.1小時延長為12.6小時。Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合使用第15天時，CsA的 AUC∞/D增加6.82倍，T1/2由5.1小時延長為17.1小時。根據模擬劑量的藥物濃度－時間曲線圖，CsA與paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合併用後，CsA劑量應調降為原先每日總劑量的七分之一，每日給予一次。7位病人皆在該藥品組合治療結束7天內調整回原使用的CsA劑量與頻次。安全性方面，病人肝功能和腎功能在併用期間皆沒有顯著的惡化。藥物不良反應則有疲勞（N=1）、頭痛（N=1），抑鬱（N=1）和腹瀉（N=1），沒有發生移植器官排斥或死亡事件。有效性方面，6位病人達快速病毒學反應（rapid virologic response, RVR），所有病人皆達治療終止時病毒學反應（end-of-treatment response, ETR）與持續性病毒學反應（SVR12）。
結論：本研究發現約有7成的臺灣器官移植病人併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合與CsA時，CsA應調降至每日總劑量的七分之一，甚至更低。應密切監測CsA的藥物谷底濃度（Ctrough）以調整後續的CsA劑量。完成該藥物組合治療後，CsA需於7天內恢復併用前的劑量頻次，且需監測Ctrough以維持CsA藥物谷底濃度在目標範圍內（50-100 ng/mL）。此外，本研究結果顯示臺灣器官移植病人使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療C型肝炎的安全性與有效性並不亞於白種人。
關鍵詞：C型肝炎、paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合、器官移植、cyclosporine、藥物動力學、亞洲人種

Background: Hepatitis C virus (HCV) infection affects millions of individuals worldwide, especially for those who have received organ transplantation. Direct-acting antiviral agents (DAAs) as a combination regimen to treat chronic HCV infection have been proven to be effective. Paritaprevir/ritonavir/ombitasvir/dasabuvir are component of the therapy regimen for HCV genotype (GT) 1 infection. It resulted in a high sustained virologic response (SVR) rate and few side effects though it needed to concern drug interaction if used on organ transplant recipients. Cyclosporine (CsA) is a key immunosuppressant after organ transplantation. Because paritaprevir/ritonavir/ombitasvir/dasabuvir regimen and CsA are both metabolized via cytochrome P450 (CYP) 3A and P-glycoprotein, coadministration of these drugs may result in serious drug interactions. Package insert of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen and recent studies suggest the CsA dose should be reduced to one-fifth of the previous total daily dose and administered once-daily when initiating paritaprevir/ritonavir/ombitasvir/dasabuvir regimen. However, we found this dose recommendation of CsA could not fit Taiwanese organ transplant recipients. Furthermore, there is a paucity of data regarding dose and frequency recommendation for CsA when paritaprevir/ritonavir/ombitasvir/dasabuvir regimen is completed. The research about the safety and efficacy of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen in Taiwanese organ transplant recipients is also absent. Thus, we conducted this study to evaluate the pharmacokinetics change of CsA. Moreover, the safety and efficacy of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen among Taiwanese organ transplant recipients taking CsA were also assessed.
Method: We conducted a retrospective study using Taipei Veterans General Hospital electronic medical records. Between January 2017 and September 2017, the patients who are organ transplant recipients under regular CsA regimen, were diagnosed with HCV infection and received paritaprevir/ritonavir/ombitasvir/dasabuvir regimen were enrolled. The non-compartmental method was used to calculate the pharmacokinetics parameters of CsA. Simulated concentration-time profile for paritaprevir/ritonavir/ombitasvir/dasabuvir regimen plus CsA to determine whether the CsA dose regimen as appropriate by using nonparametric super-positioning. The mixed effect model was utilized to assess the effect of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen on CsA and test the difference in laboratory data for the safety evaluation. The data of HCV viral load were collected for the efficacy assessment.
Result: Seven patients were enrolled into our study, including 5 kidney transplant recipients and 2 liver transplant recipients. In the presence of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen on the first day, dose-normalized CsA AUC∞ was 5.18-fold when CsA administered alone, respectively. CsA half-life increased from 5.1 to 12.6 hours. When the steady state of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen is reached, CsA dose-normalized AUC∞ were 6.82-fold of the CsA values when administered alone, and CsA half-life increased from 5.1 to 17.1 hours. From simulated concentration-time curve, a reduction in CsA dose and dosing frequency is sevenfold reduction in total daily dose to achieve Ctrough values similar to those observed before paritaprevir/ritonavir/ombitasvir/dasabuvir regimen. The readjustments of CsA for all patients were done within 7 days after the paritaprevir/ritonavir/ombitasvir/dasabuvir regimen is completed. For safety issue, there were no significant deterioration of liver and kidney function. Adverse events for fatigue in one patient, headache in one patient, malaise in one patient and diarrhea in one patient. No episode of graft rejection or patient mortality was observed during the treatment. Six patients achieved rapid virologic response (RVR), and all patients achieved end-of-treatment response (ETR) and sustained virologic response at 12 week (SVR12).
Conclusion: When initiating therapy with paritaprevir/ritonavir/ombitasvir/dasabuvir regimen, the CsA dose should be reduced to one-seventh of the previous total daily dose in 70 percentage of Taiwanese organ transplant recipients, with close monitoring of CsA Ctrough to determine subsequent dose modifications. The CsA dose should be resumed within 7 days when the paritaprevir/ritonavir/ombitasvir/dasabuvir regimen completed, followed by frequent therapeutic drug monitoring to maintain appropriate CsA concentration (50-100 ng/ml). The safety and efficacy of paritaprevir/ritonavir/ombitasvir/dasabuvir regimen in Taiwan organ transplant recipients were not inferior to Caucasians.
Key words: HCV, paritaprevir/ritonavir/ombitasvir/dasabuvir regimen, organ transplantation, cyclosporine, pharmacokinetics, Asian

目錄
致謝…………………………………………………………………………i
中文摘要……………………………………………………………………ii
英文摘要……………………………………………………………………v
目錄…………………………………………………………………………viii
圖目錄………………………………………………………………………x
表目錄………………………………………………………………………xii
縮寫表………………………………………………………………………xiv
第一章 緒論…………………………………………………………………1
第1節 研究背景與動機……………………………………………………1
第2節 研究目的……………………………………………………………18
第二章 文獻探討……………………………………………………………19
第1節 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合併用cyclosporine之藥物動力學影響………19
第2節 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合併用
cyclosporine之有效性與安全性……………………………………………21
第三章 研究方法和設計……………………………………………………22
第1節 研究項目與研究假設………………………………………………22
第2節 研究設計與研究工具………………………………………………23
第3節 藥物動力學分析方法………………………………………………37
第4節 統計方法……………………………………………………………39
第四章 研究結果……………………………………………………………41
第1節 研究對象基本資料…………………………………………………41
第2節 Cyclosporine之藥物動力學分析與劑量模擬……………………46
第3節 治療結束後殘餘paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合對cyclosporine之影響評估…56
第4節 直接作用抗病毒藥物之有效性分析………………………………59
第5節 直接作用抗病毒藥物之安全性分析………………………………61
第五章 討論…………………………………………………………………71
第1節 Cyclosporine之藥物動力學和劑量模擬與劑量建議討論………71
第2節 治療結束後殘餘paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合對cyclosporine影響之討論…80
第3節 直接作用抗病毒藥物之有效性討論………………………………82
第4節 直接作用抗病毒藥物之安全性討論………………………………84
第5節 研究限制……………………………………………………………85
第六章 結論與未來研究建議………………………………………………86
第1節 結論…………………………………………………………………86
第2節 未來研究建議………………………………………………………87
第七章 參考文獻……………………………………………………………88

圖目錄
圖 3-2-1 藥物濃度監測之分期…………………………………………27
圖 4-1-1 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療前與治療中cyclosporine藥物谷底濃度監測……………44
圖 4-2-1 Cyclosporine單獨使用藥物濃度－時間曲線圖……………50
圖 4-2-2 併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合與cyclosporine第1天藥物濃度－時間曲線圖……………50
圖 4-2-3 併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合與cyclosporine第15天藥物濃度－時間曲線圖……………51
圖 4-2-4 劑量標準化之平均藥物濃度－時間曲線圖…………………51
圖 4-2-5 Cyclosporine模擬劑量之藥物濃度－時間曲線圖…………53
圖 4-3-1 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療結束當天至治療結束後第7天cyclosporine之藥物濃度監測……57
圖 4-4-1 治療C型肝炎前後之病毒量變化趨勢圖……………………60
圖 4-5-1 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人ALT變化趨勢圖……………62
圖 4-5-2 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人AST變化趨勢圖……………62
圖 4-5-3 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人TB變化趨勢圖……………63
圖 4-5-4 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人Scr變化趨勢圖…………66
圖 4-5-5 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人eGFR變化趨勢圖…………66
圖 4-5-6 使用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合期間病人BUN變化趨勢圖…………67
 
表目錄
表 1-1-1 臺灣健保核准之直接作用抗病毒藥物……………5
表 1-1-1 臺灣健保核准之直接作用抗病毒藥物（續）……6
表 1-1-2 免疫抑制劑比較……………………………………9
表 1-1-3 Viekirax/Exviera、Daklinza/Sunvepra和Zepatier與CNIs交互作用之影響……………………………14
表 1-1-4 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合與CNIs代謝所需肝臟酵素與影響之運轉蛋白……………14
表 3-2-1 研究資料檔名稱與擷取變項………………………25
表 3-2-2 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合健保給付規定………………………………26
表 4-1-1 研究對象基本特性…………………………………42
表 4-1-1 研究對象基本特性（續）…………………………43
表 4-1-2 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療前與治療中cyclosporine劑量調整…………………45
表 4-2-1 Cyclosporine藥物動力學參數……………………47
表 4-2-1 Cyclosporine藥物動力學參數（續）……………48
表 4-2-2 併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合前後cyclosporine劑量頻次與預期cyclosporine藥物谷底濃度…53
表 4-2-3 併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合第1天之模擬cyclocporine劑量………………………………………54
表 4-2-4 併用paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合第15天之模擬cyclocporine劑量……………………………………55
表 4-3-1 Paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合結束後之cyclosporine劑量調整…………………………………………58
表 4-4-1 病人接受paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合治療中與治療後的病毒學反應…………………………………60
表 4-5-1 混合模型下paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合效果對肝功能實驗室數值影響之結果（12週療程，N=5）……64
表 4-5-2 混合模型下paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合效果對肝功能實驗室數值影響之結果（24週療程，N=2）……64
表 4-5-3 混合模型下paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合效果對腎功能實驗室數值影響之結果（12週療程，N=5）……68
表 4-5-4 混合模型下paritaprevir/ritonavir/ombitasvir/dasabuvir藥品組合效果對腎功能實驗室數值影響之結果（24週療程，N=2）……68
表 4-5-5 藥品不良反應事件與實驗室數值異常……………………………70
表 5-2-1 本研究與先前研究之幾何平均數比值數值比較…………………73
表 5-2-2 本研究與先前研究之藥物動力學參數比較………………………73
表 5-2-3 本研究與先前研究之劑量調整比較………………………………74

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