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系統識別號 U0007-0707201114014200
論文名稱(中文) Felodipine緩釋錠劑於國人之藥動學特性及族群因素在銜接性試驗之評估研究
論文名稱(英文) Pharmacokinetics of Felodipine Extended Release Tablets in Healthy Taiwanese Subjects and Evaluation of Ethnic Sensitivity Data in Bridging Study
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(博士班)
系所名稱(英) Pharmacy (PhD)
學年度 99
學期 2
出版年 100
研究生(中文) 蕭嘉玲
研究生(英文) Chia-Ling Hsiao
學號 D301091003
學位類別 博士
語文別 中文
口試日期 2011-06-30
論文頁數 110頁
口試委員 指導教授-許光陽
委員-陳恆德
委員-鮑力
委員-許秀蘊
委員-吳姿樺
中文關鍵字 Felodipine  藥物動力學  台灣人  CYP3A4  族群差異  銜接性試驗  亞洲族群資料  ICH E5 
英文關鍵字 Felodipine  Pharmacokinetics  Taiwanese  CYP3A4  Ethnic difference  Bridging study  Asian data  ICH E5 
學科別分類
中文摘要 本研究主要研究felodipine於國人的藥動學特性。資料來源為回溯性分析於國內執行的五個felodipine生體相等性試驗,共收納100人。受試者服用5 mg(n = 80)或10 mg(n = 20) Plendil®(felodipine extended-release tablets; felodipine ER)連續6日。劑量校正為10 mg felodipine後,100人的tmax, ss、Cmax,ss、AUC0-tau?鉹嬪O為3.32 hr, 13.12 nmol/L and 136.33 nmol*hr/L。本研究顯示AUC/dose、Cmin/dose、CL/F不呈現常態分佈,且依據AUC/dose可區分成兩個不同CYP3A4代謝速率的族群。與文獻相較,給予我國健康男性年輕受試者5 mg felodipine ER後,其全身性暴露量與瑞典、丹麥、土耳其、加拿大健康受試者服用10 mg felodipine ER相似或略低;Cmax與德國年長受試者相似,而AUC較低約30%。顯示我國族群可能具有較低的CYP3A4代謝活性,此現象與nifedipine相似。
我國於90年1月1日開始施行銜接性試驗評估,其主要評估是否可接受外國臨床試驗資料外推至我國族群。評估概念主要依據國際法規協合會E5基準。本研究中,無論同一件銜接性試驗評估申請案申請次數,皆以一件計算。自90年1月1日起至99年6月30日止,共有366件銜接性試驗申請案件。平均免除率為73.8%。本研究中依據化學藥品/生物製劑、適應症、新藥類別、給藥途徑及完整臨床試驗是否包含亞洲族群臨床資料進行類別分析。並分析銜接性試驗申請案第一次申請未獲同意免除銜接性試驗之理由,以及廠商再次重新送件後,其免除率之分析。亞洲人之藥動學資料多數為日本人之藥動學試驗結果,其他依序為中國、台灣、韓國等。若完整臨床試驗資料中包含亞洲族群藥動學資料及臨床療效性及安全性資料,對於免除銜接性試驗相當有幫助。在某些情況下,若有藥品的安全性及/或有效性方面的族群差異性疑慮,可以上市後第四期(phase IV)臨床試驗取代銜接性試驗。
英文摘要 The objective of this study was to investigate the pharmacokinetics of felodipine (CAS number: 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine bioequivalence studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. Subjects received 5 mg (n=80) or 10 mg (n=20) of Plendil® (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean tmax,ss, Cmax,ss and AUC0-tau of dose-normalized to 10 mg felodipine was 3.32 hr, 13.12 nmol/L and 136.33 nmol*hr/L, respectively. By using Kolmogorov-Smirnov’s test and probit plots, results indicated that the frequency distribution of AUC/dose, Cmin/dose and CL/F was bimodal. Compared to data from the literature, the mean Cmax,ss and AUC of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable Cmax values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.
The assessment of the acceptability of the extrapolation of foreign clinical data to a new region for registration purpose, known as the process of “bridging study evaluation”, started in Taiwan on January 1, 2001. The review process was based on the International Conference on Harmonization E5 guideline. If one drug counted as one time no matter its submission times, 366 cases were collected and the rate of bridging study waiver was 73.8%. The percentage of waiver of each category was studied. The reasons for not granting the BSE waiver at their first time submission were identified. Japanese pharmacokinetic data were the majority of Asian pharmacokinetic data, followed by Chinese, Taiwanese, Asian populations (not identified), Korean, subjects in Hong Konger, Malaysians. Complete clinical data package contained Asian PK and clinical efficacy is helpful to waive the bridging study. Under some conditions, it is satisfactory that ethnic concern in safety and efficacy might be answered by phase IV study.
論文目次 中文摘要 I
Abstract III
目錄 V
表目錄 VIII
圖目錄 X
縮寫檢索表 XIII
第一章 緒論 1
第一節 引言 1
第二節 Nifedipine族群差異性之文獻回顧 4
第三節 Felodipine藥動特性之文獻回顧 6
第四節 銜接性試驗評估之緣由 11
第五節 我國實施銜接性試驗評估之歷史 15
第六節 研究目的 20
第二章 研究材料與方法 22
第一節 研究族群 22
第二節 試驗設計 23
第三節 Felodipine血中濃度分析方法 24
第四節 藥動參數解析方法 25
第五節 統計分析方法 27
第六節 銜接性試驗案件 29
第三章 研究結果 34
第一節 人口統計資料 34
第二節 安全性評估 35
第三節 生體含量分析方法確效 35
第四節 藥動學參數 36
第四節 銜接性試驗案件類別分析 49
第五節 重新檢送銜接性試驗案件分析 54
第六節 新成份新藥於亞洲人與非亞洲人之藥動參數比較 58
第四章 討論 72
第一節 Felodipine國人數據之收集 72
第二節 Felodipine分析方法 72
第三節 Felodipine藥物動力學 73
第三節 銜接性試驗案件類別分析 83
第四節 重新檢送銜接性試驗案件分析 86
第五節 新成份新藥於亞洲人與非亞洲人之藥動學參數比較 89
第五章 總結 93
參考文獻 95
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