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系統識別號 U0026-1906201400155800
論文名稱(中文) 定量藥理學的模型建構與模擬之應用
論文名稱(英文) Application of Pharmacometric Modeling and Simulation
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 102
學期 2
出版年 103
研究生(中文) 徐立峰
研究生(英文) Li-Feng Hsu
學號 S68001024
學位類別 博士
語文別 中文
論文頁數 119頁
口試委員 指導教授-黃金鼎
口試委員-周辰熹
召集委員-蔡瑞真
口試委員-李勇進
口試委員-胡德民
中文關鍵字 定量藥理學  類風濕性關節炎  美國風濕病學會20/50/70反應率  28處關節疾病活動度積分值  藥物動力學/藥物藥效學的模型建構與模擬  微脂粒藥品  生體相等性  蒙地卡羅模擬方法 
英文關鍵字 Pharmacometrics  Rheumatoid arthritis  ACR20/50/70  DAS28  PK/PD modeling and simulation  Liposome drug product  Bioequivalence  Monte Carlo simulation 
學科別分類
中文摘要 試驗目的:
在本論文中主要是以定量藥理學的研究方法,探討在臨床療效以及生體相等性試驗評估上的實際應用。第一部份的試驗將以藥物動力學藥物藥效學 (pharmacokinetic/pharmacodynamic, PK/PD)的模型建構與模擬之方法,探討etanercept在治療類風濕性關節炎病患時,降低給藥劑量方案的可行性。第二部份的試驗則將會是以藥物動力學模型進行蒙地卡羅模擬 (Monte Carlo simulation),探討在評估微脂粒藥品的生體相等性 (bioequivalence, BE)試驗時,何種分析物 (總和型、包埋型或游離型)較適宜作為BE試驗的評估指標。
研究方法:
第一部份試驗中使用的所有數據,皆收集自目前已發表的文獻當中。主要的臨床試驗指標是選擇美國風濕病學會 (American College of Rheumatology, ACR)20/50/70 反應率與28處關節疾病活動度 (disease activity score in 28 joints, DAS28)積分值。試驗的步驟是先針對etanercept血清濃度數據進行PK模型的擬合,並以最後的模型參數估算不同給藥方案etanercept的累積曲線下面積 (area under the curve, AUC),再藉此建立與ACR20/50/70反應率以及DAS28積分值的PK/PD模型。本次試驗是利用最後所建立的PK/PD模型,針對10種不同的給藥方案進行模擬評估。
在第二部份試驗中,我們提出了一套微脂粒分類系統,將微脂粒藥品依照網狀內皮系統 (reticuloendothelial system, RES)的攝取程度與體內釋放速率,區分為以下四大類: class I:RES攝取程度低釋放速率快速;class II: RES攝取程度低釋放速率緩慢;class III: RES攝取程度高釋放速率快速;class IV: RES攝取程度高釋放速率緩慢。結合這樣分類系統的概念,我們模擬了各種不同微脂粒藥品的類型,並藉此評估何種分析物,在BE試驗的評估中具有較佳的鑑別能力。所有的藥物類型都會在單一劑量與重複劑量試驗設計下進行探索研究。最終則是依照檢定力曲線 (power curve)的結果來判斷分析物的敏感性。
試驗結果:
第一部份的試驗結果顯示,一級吸收與排除速率的一室模型是能夠提供etanercept血清數據的最佳擬合結果。依據PK/PD模型的分析結果,分別以邏輯最大效應迴歸模型 (logistic-Emax model)與最大抑制效應模型 (inhibitory Emax model),是能夠適當的描繪etanercept累積AUC與ACR20/50/70反應率以及DAS28積分值之間的關聯性。依據劑量模擬結果,本次試驗提出下列與目前etanercept建議劑量 25 mg每週二次相同臨床療效的給藥方案:(1) 25 mg每週一次;(2) 50 mg每兩週一次;(3)前3個月先給予25 mg每週兩次,此後再給予25 mg每兩週一次;與(4)前3個月先給予50 mg每週一次,此後再給予50 mg每兩週一次。
第二部份的模擬結果顯示,對於RES攝取程度低的微脂粒藥品而言 (class I 與class II微脂粒藥品),包埋型是一個較佳的BE試驗評估指標。對於RES攝取程度高的微脂粒藥品而言 (class III 與class IV微脂粒藥品),游離型則是一個較佳的BE試驗評估指標。唯有當微脂粒藥品屬於RES攝取程度低且釋放速率緩慢的情況 (class II微脂粒藥品),總和型才能作為一個評估BE試驗的選擇。除非有其他倫理上的考量必須要針對病患執行重複劑量試驗,一般而言單一劑量試驗就足以用來證實最後BE的結果。
結論:在本試驗中我們利用了藥物動力學/藥物藥效學模型,評估etanercept使用於RA病患時劑量降低的可能性,並且提出了四種不同的替代給藥方案。另外,針對微脂粒藥品的BE試驗,我們也以藥物動力學模型進行蒙地卡羅的隨機模擬,提出一個較佳的評估指標與試驗設計。本試驗說明了定量藥理學的研究在藥物治療和研發方面具有極佳的應用性。
英文摘要 Part I: In this study, we attempt to explore the feasibility of alternative dosing regimens of etanercept in patients with rheumatoid arthritis (RA) using pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. All data used for estimation of PK/PD model parameters were collected from previously published literatures. American College of Rheumatology (ACR) 20/50/70 response rate and a disease activity score in 28 joints (DAS28) was selected as the principal clinical endpoint for further PK/PD modeling. The cumulative AUC (area under the curve) of etanercept for different dosing regimens was calculated based on the final PK model and was then linked to the time course of clinical endpoints. Ten different dosing regimens were simulated in this study. The PK model that best fit the serum concentration-time data for etanercept was a one-compartment model with first order absorption and elimination. Based on the PK/PD analysis, the relationship between the predicted cumulative AUC of etanercept to the ACR 20/50/70 response rate and DAS28 score was well characterized by Emax logistic and inhibitory Emax model, respectively. In our simulations, the following dosing regimens that are equally effective to current recommended dosage of 25 mg twice weekly (biw): (1) 25 mg once weekly (qw); (2) 50 mg every two weeks (q2w); (3) 25 mg biw for 3 months and 25 mg q2w thereafter; and (4) 50 mg qw for 3 months and 50 mg q2w thereafter. In this study, the clinical data was well described by the models developed, and several alternative dosing regimens were proposed. Further clinical studies in patients are still needed to confirm our findings.

Part II: The purpose of the study was to identify the most sensitive analyte (i.e., encapsulated, free, and total forms) for assessing the bioequivalence (BE) of liposome drug products using Monte Carlo simulation. We proposed a liposome classification system that divided liposome drug products into four classes according to the extent of reticuloendothelial system uptake and in vivo release rate: Class I - low reticuloendothelial system uptake-rapid release rate; Class II - low reticuloendothelial system uptake-slow release rate; Class III - high reticuloendothelial system uptake-rapid release rate; Class IV - high reticuloendothelial system uptake-slow release rate. In conjunction with the proposed classification scheme, a variety of drug classes were simulated to determine which analyte provides the most sensitive measure of BE. All drug classes were investigated in single and multiple dose studies. The sensitivity of analytes for measuring BE was evaluated using the power curve. Our simulations indicated the encapsulated form provides the most accurate assessment BE for liposome drug products with low reticuloendothelial system uptake (i.e., class I and II). For liposome drug products with high reticuloendothelial system uptake (i.e., class III and IV), the free form provides the best indication BE. Measurement of total drug form to assess BE was preferred only for liposome drug products with low reticuloendothelial system uptake and slow release rates (i.e., class II liposomal drug product). In general, a single dose form is sufficient for demonstrating the BE of liposome drug products.
論文目次 中文摘要 I
Extended Abstract IV
致謝 XIV
目錄 XVI
圖目錄 XIX
縮寫指引 XXI
第一章 序言 1
第二章 以藥物動力學/藥物藥效學模型評估etanercept使用於類風濕性關節炎病患之劑量降低策略 3
第一節 文獻回顧 4
一、類風濕性關節炎 4
(一)、簡介 4
(二)、治療策略與方向 5
(三)、生物製劑的健保給付現況 7
二、臨床療效評估指標 7
(一)、美國風濕病學會反應標準 7
(二)、28處關節疾病活動度評估 8
(三)、歐洲抗風濕病聯盟反應標準 9
三、生物製劑 10
(一)、Etanercept簡介 10
(二)、臨床療效與副作用 11
第二節 研究目的 13
第三節 研究設計 14
一、數據收集 14
二、臨床試驗指標 15
三、藥物動力學分析 15
四、ACR20/50/70反應率模型 16
五、DAS28積分值模型 16
六、模型評估 17
七、不同劑量方案的模擬 17
第四節 研究結果 19
一、試驗特性 19
二、藥物動力學分析 21
三、藥物動力學與ACR20/50/70反應率的關聯性 23
四、藥物動力學與DAS28積分值的關聯性 26
五、不同劑量方案的模擬 29
第五節 討論 35
第六節 小結 39
第三章 以統計分析方法評估微脂粒學名藥產品的生體相等性關鍵參數 40
第一節 文獻回顧 41
一、微脂粒 41
(一)、簡介 41
(二)、微脂粒藥品之研發市場 42
二、微脂粒藥品之藥物動力學 45
(一)、分析物的命名 45
(二)、分布與排除特性 45
(三)、劑型對於藥物動力學的影響 47
三、微脂粒產品之生體相等性評估 50
(一)、生體相等性評估 50
(二)、各國的法規建議 51
四、蒙地卡羅模擬在生體相等性試驗研究的應用 52
第二節 研究目的 54
第三節 研究設計 55
一、藥物動力學模型 55
二、微脂粒分類系統 56
三、生體相等性試驗的模擬 59
四、統計分析與檢定力曲線 60
第四節 研究結果 61
第五節 討論 73
第六節 小結 80
第四章 結論 81
第五章 參考文獻 82
附錄一 95
附錄二 97
附錄三 98
附錄四 99
附錄五 105
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