盐酸贝那普利片的人体相对生物等效性及药物动力学研究

目的比较国产盐酸贝那普利片在20名健康志愿者体内的药物动力学特征及相对生物利用度,评价其生物等效性.方法20名健康男性志愿者采用随机交叉给药方案,分别单剂量口服20 mg的盐酸贝那普利片,采用高效液相色谱/质谱/质谱联用的方法测定贝那普利及其活性代谢产物贝那普利拉的血药浓度,计算两者的药代动力学参数及相对生物利用度.结果经3p87模型拟合,口服盐酸贝那普利20mg后,贝那普利的主要药物动力学参数为:α为(4.79±6.73)/h,β为(0.95±0.61)/h,Ka为(10.52±11.11)/h,V/f(c)为(121±58)L,t1/2α为(0.24±0.11)h,t1/2β为(0.39±2.12)h,K21为(1.22±0.79)/h,K10为(4.06±6.72)/h,K12为(0.46±0.52)/h,AUC为(72.88±20.51)μg·h/L,Cl(s)为(0.30±0.10)L/h,T(peak)为(0.39±0.12)h,Cmax为(89.61±25.31)μg/L,MRT0-∞为(0.85±0.23)h.其活性代谢产物贝那普利拉的主要药物动力学参数α为(0.37±0.10)/h,β为(0.06±0.07)/h,Ka为(1.89±0.45)/h,V/f(c)为(220±30)L,t1/2α为(1.99±0.52)h,t1/2β为(5.91±7.90)h,K21为(0.10±0.09)/h,K10为(0.26±0.05)/h,K12为(0.07±0.06)/h,AUC为(359.83±79.95)μg·h/L,Cl(s)为(0.06±0.01)L/h,T(peak)为(1.84±0.50)h,Cmax为(58.68±13.06)μg/L,MRT0-∞为(8.16±1.16)h.受试制剂的相对生物利用度为(109.6±13.2)%.结论统计学结果显示,两种片剂具有生物等效性.     

双氯芬酸钾缓释片在家犬体内的药动学及生物等效性研究

 目的对自制双氯芬酸钾缓释片和市售双氯芬酸钾普通片进行家犬体内的生物等效性评价。方法6条家犬按标准的2×2交叉试验方案设计,禁食12 h后空腹口服普通片剂(参比制剂)50 mg或缓释片剂(供试制剂)75 mg;采用RP-HPLC紫外检测法检测血浆中药物浓度,并计算相关的药动学参数,判定两制剂是否生物等效。结果参比制剂及供试制剂的主要药动学数据如下:t_max分别为(0.50±0.01)和(4.17±0.10)h;ρ_max分别为(4.96±1.06)和(1.37±0.11)mg·L^-1;AUC_0～∞分别为(9.09±0.89)和(12.86±0.70)mg·h·L^-1;t_1/2分别为(2.33±0.84)和(7.94±1.45)h。结论两种制剂的主要药动学参数ρ_max和AUC_0～∞经对数转换后进行方差分析及双单侧t检验,并计算90%置信区间,表明两种制剂为以AUC为评价指标的生物等效制剂,相对生物利用度为97.16%,供试制剂与参比制剂相比具有良好的缓释效果。     

雷米普利胶囊人体生物等效性研究

 目的评价国产雷米普利胶囊与已上市的雷米普利片的人体生物等效性。方法18名男性健康志愿者随机交叉po雷米普利受试制剂和参比制剂各10 mg,采用液相色谱-质谱法同时测定雷米普利及其活性代谢物雷米普利拉的药物浓度。结果参比制剂及受试制剂的雷米普利的t_max分别为(0.53±0.14)和(0.58±0.17)h,ρmax分别为(42.34±13.37)和(43.84±13.65)μg·L^-1,AUC_0-72分别为(41.70±13.62)和(42.57±11.54)μg·h·L^-1,t_1/2(ke)分别为(2.55±1.55)和(2.40±0.85)h,雷米普利拉的t_max分别为(2.44±0.62)和(2.50±0.51)h,ρ_max分别为(43.28±13.83)和(39.75±13.73)μg·L^-1,AUC_0-72分别为(311.34±99.34)和(312.34±97.74)μg·h·L^-1,t_1/2(ke)分别为(18.80±6.82)和(17.99±5.94)h,国产雷米普利胶囊相对生物利用度以雷米普利计为(104.44±13.07)%,以雷米普利拉计为(101.62±14.56)%。结论方差分析和双单侧t检验结果表明,两种制剂生物等效。     

Bioequivalence Between rhGH for Reconstitution and Ready-to-Use rhGH in Two Liquid Formulations

Bioequivalence Between rhGH for Reconstitution and Ready-to-Use rhGH in Two Liquid Formulations     

甲硝唑片人体生物等效性研究

目的评价甲硝唑片的生物等效性。方法将20名健康男性志愿者随机分为两组,分别交叉口服两种甲硝唑片,采用高效液相色谱法测定血药浓度;以3P97软件计算药代动力学参数,用方差分析和双单侧t检验及(1-2α)置信区间法分析两种甲硝唑片是否等效。结果单剂量口服600mg受试制剂和参比制剂,达峰时间(Tmax)为(1.425±0.373)h和(1.5±0.281)h,血药峰浓度(Cmax)为(8.999±0.800)μg/mL和(9.226±0.788)μg/mL;0～48h药时曲线下面积(AUC0→48)为(157.285±15.526)mg·h/L和(151.760±16.718)mg·h/L,受试制剂的相对生物利用度为(104.0±10.1)%。结论两种甲硝唑片具有生物等效性。     

阿奇霉素分散片的人体药物动力学和生物等效性研究

20名健康男性志愿者交叉口服两种国产阿奇霉素分散片的受试制剂和参比制剂500mg,以HPLC-MS法测定血浆中阿奇霉素的浓度,研究人体药物动力学参数和生物等效性。采用C_8柱,流动相为甲醇-0．02mol／L乙酸铵溶液(70:30), 受试制剂和参比制剂的C_(max)分别为(472．14±216．37)和(432．96±131．80)ng／ml t_(1／2)分别为(68．63±12．93)和(70．63± 15．61)h;T_(max)分别为(2．18±0．89)和(2．25±0．84)h; AUC_(o→144h)分别为(4268．52±1252．89)和(4370．32±807．82)ng·h·ml~(-1)。经方差分析和双单侧t检验,说明两片剂具有生物等效性,受试制剂的相对生物利用度为(97．1±22．7)％。     

托烷司琼胶囊和片剂的药物动力学和生物等效性研究

21名男性健康受试者三交叉口服托烷司琼受试制剂(胶囊A、片剂B)和参比制剂(胶囊C),进行药物动力学及生物等效性研究。采用HPLC/MS/MS测定血浆中托烷司琼浓度。A、B和C三者的Cmax分别为(44.6±17.7)、(43.9±14.9)和(39.1±13.6)ng/ml,AUC0→48h分别为(673.9±511.3)、(668.6±479.8)和(597.1±462.3)ng·h·ml-1。A、B的相对生物利用度分别为(114.1±20.9)%、(114.8±9.0)%,三者具有生物等效性。     

头孢克肟胶囊的药物动力学及生物等效性研究

18名健康受试者单剂量交叉口服两种头孢克肟胶囊,进行药物动力学和生物等效性研究。采用HPLC法测定人血浆中头孢克肟的浓度。受试制剂和参比制剂的AUC0-∞分别为(18.22±3.79)和(18.68±3.67)μg·ml-1·h,Cmax分别为(2.10±0.36)和(1.98±0.36)μg/ml,t1/2分别为(3.65±0.81)和(3.78±0.66)h。双单侧t检验结果表明,两种头孢克肟胶囊具有生物等效性。     

Subject-by-Formulation Interaction in Bioequivalence: Conceptual and Statistical Issues

Purpose. The FDA has proposed replacing the current averagebioequivalence criterion with population and individual bioequivalence criteriathat consider variances in addition to the difference of averages. Oneof these variances in the individual bioequivalence criterion measuressubject-by-formulation interaction, the extent to which thetest-reference difference varies from person to person. This paper discussesconceptual and statistical issues raised in various publications andpresentations with respect to the presence and estimation of such aninteraction. Methods. We focus on the importance of subject-by-formulationinteraction, an understanding of what is a large interaction, and theassessment of the magnitude of this interaction in bioequivalence studies.Simulation studies, examples from the literature, and data from FDAfiles are used to demonstrate the magnitude of the interaction and itsdistribution under various conditions. Results. The concept of a large interaction is tied to the concept of alarge mean difference. We suggest that an interaction greater than0.15 is a conservative criterion for a large interaction. Magnitudes ofestimated interaction are affected by variability, sample size, and theselection of data sets that pass average bioequivalence. Conclusions. Examples of substantial interactions are beginning toappear. More data is needed before reaching definitive conclusionsregarding the frequency and importance of observed interactions.     

Bioequivalence Study of Stressed and Nonstressed Hard Gelatin Capsules Using Amoxicillin as a Drug Marker and Gamma Scintigraphy to Confirm Time and GI Location of In Vivo Capsule Rupture

Purpose: Evaluate if crosslinked hard gelatin capsules (HGCs) havingdifferent in vitro dissolution profiles changed in vivo release times oraltered bioavailability of a drug marker; assess if a two-tier dissolutiontest (with and without enzyme) predicted in vivo performance. Methods. Two classifications of stressed HGCs were artificiallyproduced by exposure to formaldehyde (HCHO). HGCs were categorizedas, a) pass/pass (p/p) which met in vitro dissolution criterion (75%drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p)which failed dissolution criterion in the absence of enzymes and passedin the presence of enzymes, and c) severely crosslinked fail/fail (f/f)which failed in vitro standards with or without enzymes. A six-way,single dose bioequivalence study (n = 10) administered the three HGCsunder the fasted and fed condition. In vivo capsule rupture and GItransit were monitored via gamma scintigraphy, and blood sampleswere collected through six hours. Results. Each crosslinked HGC was bioequivalent to the control p/pcapsule when using AUC(0–) and Cmax for comparison. Meanin vivo disintegration of the p/p capsule was 7 ± 5 min for the fastedcondition and 11 ± 7 min for the fed condition. In vivo rupture forthe f/p capsule was 22 ± 12 min and 23 ± 11 min for the fasted andfed studies, respectively, while the f/f HGC ruptured at 31 ± 15 minand 71 ± 19 min under the fasted and fed condition, respectively.Onset of amoxicillin absorption was dependent on in vivo HGC ruptureand subsequent entry of the released radioactive marker into the smallintestine. Consequently, fasted Tmax values were significantly laterfor the f/p HGC (1.62 ± 0.53 hr) and f/f HGC (1.85 ± 0.58 hr) ascompared to the p/p HGC (1.17 ± 0.30 hr). Fed Tmax values werestatistically different only for the f/f capsule (2.55 ± 0.44 hr) whereTmax values for the p/p and f/p HGCs under the fed condition were1.50 ± 0.47 hr and 1.60 ± 0.46 hr, respectively. Conclusions. A two-tier dissolution procedure that retested across-linked hard gelatin capsule with addition of gastric or intestinal enzymesprovided an adequate in vitro indicator of the formulation'sin vivo performance. The observed delays in the onset of amoxicillin absorptionand Tmax for the severely crosslinked f/f HGC was attributed todelayed in vivo capsule rupture, however, this delay did not adverselychange AUC(0–) nor Cmax.