劉仁沛臺灣大學:農藝學研究所蔡蓓瑩Tsai, Pei-YingPei-YingTsai2010-05-052018-07-112010-05-052018-07-112009U0001-2707200914270400http://ntur.lib.ntu.edu.tw//handle/246246/180140由於鼻藥噴霧劑(Nasal aerosols)與鼻腔噴霧器(Nasal sprays)之噴霧藥效皆為局部性作用藥品，不易藉由血液的流動進入人體器官中，因此我們利用藥劑生體可用率(Bioequivalence)與生體相等性(Bioequivalence)的機器實驗來評估兩種藥物的藥效性是否相等。美國食品與藥物管理局(簡稱FDA)(2003b)，提出以95%信賴上界來作為比較兩種藥物的生體相等性(Bioequivalence)之標準。Hyslop, Hsuan和Holder首先在2000年將此標準線性化並提出相對應之統計方法。因在評估噴霧器實驗有批次、生命階段與檢體等不同變因，我們根據二階段巢式隨機模式的變方分析之大樣本修正法(MLS)來尋求線性化準則95%信賴上限。最後利用各種樣本數及不同變異數組合下之模擬資料，以經驗型I誤差和經驗檢定力來評估由延伸之變方分析大樣本修正法(MLS)是否能求得一個較佳的95%信賴上界。最後我們以一個實例介紹本方法在實務上之應用。For some locally acting products such as nasal aerosols and nasal sprays that are not intended to be absorbed into the bloodstream, the in vitro bioavailability / bioequivalence studies based on machinery experiments are used to measure that whether the two drug products provide the same therapeutic effect. According to the U.S. Food and Drug Administration (FDA) draft guidance (2003b), the evaluation of the in vitro bioequivalence (BE) between two drug products would be determined by comparing the upper 95% confidence limit of with zero. This method was first proposed by Hyslop, Hsuan and Holder (2000) based on a linearized bioequivalence criterion. However, their method does not consider the variations due to different sources. Hence, we apply the method of modified large-sample (MLS) for the variance components under the 2-stage nested random-effects model for construction of the upper 95% confidence limit. The total variance of the 95% upper limit considers the variance components due to lot, life stage and sample which are obtained through the MLS method. The results of empirical size and empirical power from simulation under different sample size and variance combinations are provided to investigate the performance of the extended MLS method. A numerical example illustrates the proposed method.Chapter 1Introduction...................................1hapter 2 Study Design and Data Collection Of In Vitro Bioequivalence..........................................3.1 Study Design for In Vitro Studies...................3.2 Tests and Metrics...................................4.2.1 Emitted Dose Uniformity, Priming/Re-Priming, and Tail-Off Profile.................................................4.2.2 Droplet Size Distribution (DSD)...................6.2.3 Spray Pattern.....................................7.2.4 Plume Geometry....................................8hapter 3 Statistical Methods3.1 In Vitro Bioequivalence BE) Data..............................................10.1 In Vitro Bioequivalence (BE) Data..................10 .2 Nonprofile Analysis Using a Confidence Interval pproach...............................................11.2.1 The Linear Statistical Model of Two-Stage Nested esign.................................................11.2.2 The Bioequivalence Criterion for Comparison......13.2.3 Confidence Interval Method.......................14 .2.4 Hypothesis of the Criteria.......................15.2.5 Bioequivalence Upper Limit.......................16.3 MLS Confidence Interval for Variance Components....17.3.1 MLS Method with Extension to Dependent Estimators f Variance Components.................................18.3.2 BE Tests Based on MLS Method.....................20hapter 4 Example......................................30.1 Research Design....................................30.2 Statistical Analysis...............................31.2.1 Estimations for Linearized Criteria..............32.2.2 The 95% Upper Confidence Bounds for Linearized riteria...............................................34.3 Results Based on MLS Method........................38hapter 5 Simulation Study.............................52.1 Simulation Process.................................52.2 Simulation Results.................................53.2.1 Empirical size...................................53.2.2 Empirical power..................................54hapter 6 Discussion and Conclusion....................63eferences.............................................72ppendix A.............................................74application/pdf1652829 bytesapplication/pdfen-US鼻藥噴霧劑鼻腔噴霧器生體可用率與生體相等性95%信賴上界大樣本修正法變方分析Nasal AerosolsNasal SpraysIn Vitro Bioequivalence and BioavailabilityUpper 95% Confidence LimitMLSVariance Componentsthesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/180140/1/ntu-98-R96621203-1.pdf