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系統識別號 U0026-2208201414151600
論文名稱(中文) 口服固體速放劑型藥品體內暴露之高效率評估:以Metformin 生體相等性試驗豁免考量為例
論文名稱(英文) Efficient Estimation of Exposure for Immediate Release Solid Oral Dosage Forms: Biowaiver Considerations for Metformin
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) 邱瓊儀
研究生(英文) Chiung-Yi Chiu
學號 s66011057
學位類別 碩士
語文別 中文
論文頁數 81頁
口試委員 指導教授-周辰熹
口試委員-蔡瑞真
口試委員-鄭靜玲
中文關鍵字 metformin  生體相等性  AUCinf  Cmax  單點替代參數 
英文關鍵字 metformin  bioequivalence  biowaiver  AUCinf  Cmax  single point sampling 
學科別分類
中文摘要 簡介
國際間醫藥藥政管理機構對人體臨床試驗的倫理原則,均朝向盡可能地減少不必要的臨床試驗(包括生體相等性試驗)。但訂定相關藥品基本的查驗登記產品品質以及療效要求,與訂定相關臨床試驗豁免之依循準則,二者之間的平衡權量,則是各國之醫藥管理機構須縝密思量之處。
Metformin在臨床用於治療第二型糖尿病,使用量相當大。本研究選擇該藥品進行研究分析,以生物藥劑學分類系統(Biopharmaceutics Classification System, BCS)為基礎概念進行生體相等性試驗豁免(biowaiver)可行性研究。
此外,考量血中濃度曲線下面積(AUC)以及最高血中濃度(Cmax)是評估藥品生體相等性的兩個重要暴露參數,且估算AUC及Cmax通常需要一連串血液採樣以及檢品定量分析,相當費時也耗費成本。故本研究將探討利用metformin單點血中濃度作為評量藥品體內暴露參數,進一步有效預測生體相等性之可行性。
研究目的
建立 metformin biowaiver monograph並探討利用單點血中濃度作為評量藥品血中暴露與生體相等性的可行性。
研究方法
1. 蒐集國內外metformin相關的文獻報告,包含物化、生物藥劑、製劑配方、藥動藥效以及臨床相關資料,統合彙整。解析各因素對於metformin於體內藥物動力學參數的影響以及臨床使用相關風險評估,以建立biowaiver monograph。
2. 蒐集國內外metformin口服速放固體製劑(單方或複方)生體相等性試驗報告之原始數據。藥品血中暴露參數與各採樣時間點之血中濃度的關聯性以線性回歸求得,並藉由決定係數 (r2)、平均預測誤差、平均絕對誤差以及均方根誤差等參數判定最佳採樣點;再以最佳採樣時間點之濃度來代替AUCinf及Cmax,作為評估生體相等性試驗之參數並進而計算其相關的90%信賴區間。 

研究結果
1. 根據目前彙整的500 mg 口服速放固體劑型上市產品資料以及相關文獻建立此套biowaiver monograph。根據其溶解度(solubility)以及穿透度(permeability)表現,metformin HCl 屬BCS class III藥物。Metformin的藥物吸收代謝並無重大族群差異,目前所查詢到產品中使用的賦形劑對metformin體內吸收並無明顯的影響,且病人使用未達生體相等性標準產品的臨床風險低。經綜合評估後,metformin 500 mg口服速放固體劑型產品,若可達快速溶離(rapid dissolving),且符合此monograph所載的情形,是可建議以體外試驗取代生體相等性試驗。
2. 所蒐集彙整生體相等性試驗報告的實際試驗數據以及模擬情境經分析後顯示,於metformin給藥後2.5小時 (C2.5)與4小時(C4)的血中濃度分別和Cmax與AUC具有較佳的關聯性。且生體相等性數據經統計分析結果,以單點替代參數C2.5及C4所求得個別試驗之90%信賴區間以及相等性之判定也和以Cmax及AUC 所估算者有相當的一致性。
研究結論
在符合monograph情況下,metformin口服速放固體劑型500 mg產品若可達快速溶離,可建議豁免其生體相等性試驗研究。另外,單點血中濃度C2.5及 C4確實可分別預測metformin在體內的最高血中濃度(Cmax)與全身性暴露程度(AUCinf ),進而作為評估其生體相等性之有用且有效率的方法。
英文摘要 The purpose of the study was firstly to draft a biowaiver monograph for metformin hydrochloride immediate release (IR) solid oral dosage forms, after thoroughly considerations on its biopharmaceutical properties and the risk of waiving in vivo bioequivalence (BE) testing in the approval of new IR solid oral dosage forms containing metformin, including both reformulated products and new, multisource products. Briefly, all pertinent data available from literature sources were evaluated to assess the risk of such a biowaiver (risk being defined as both the chance of arriving at an incorrect biowaiver decision, and an assessment of the likely impact of such an incorrect biowaiver decision on public health and individual patient risks) and suggested whether a biowaiver can be recommended or not.
Secondly, an efficient in vivo single-point sampling method for assessment of oral metformin exposure and BE was proposed to overcome the limitation of in vitro study and the cost of full course of BE study. According to the result of data analysis on a total of 154 concentration-time profiles from 77 healthy volunteers who participated in six BE studies and ten scenarios of Monte Carol simulation data (200 BE studies of 24 subjects), it was find that the concentrations of 2.5 and 4 hours sampling time have good correlation with Cmax and AUC, respectively, and are good surrogate parameters for BE assessment.
論文目次 目錄
中文摘要 i
Extended Abstract iii
致謝 vi
目錄 vii
表目錄 viii
圖目錄 xi
第壹章 序言 1
第貳章 Metformin HCl口服固體速放劑型之生體相等性試驗豁免研究 2
第一節 研究目的 2
第二節 研究設計 4
第三節 研究結果 4
第四節 討論 13
第參章 以單點採樣法評估口服metformin體內暴露參數及生體相等性 15
第一節 研究目的 17
第二節 研究材料 17
一、 藥品生體相等性試驗報告數據 17
二、 繪圖及藥動分析軟體 19
第三節 研究方法 20
一、 生體相等性試驗報告數據分析 20
二、 模擬數據分析 21
第四節 研究結果 25
一、 生體相等性試驗報告數據分析 25
二、 模擬數據分析 37
第五節 討論 70
一、 生體相等性試驗報告數據分析 70
二、 模擬數據分析 71
三、 小結 75
第肆章 結論 76
參考文獻 77
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