Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.     

Relative bioavailability of four controlled-release nifedipine products

Four controlled-release nifedipine products were investigated in two clinical studies. In study 1, 22 healthy male volunteers took part in an open, multiple-dose, randomized, crossover study to determine the relative bioavailablity of two 10 mg controlled-release nifedipine tablet (Adalat® Retard, Bayer), administered 12 hourly, and one 20 mg controlled-release nifedipine tablet (Adalat® Retard, Bayer) administered 12 hourly. In study 2, 24 healthy male volunteers took part in an open, multiple-dose, randomized, three-period, crossover study to determine the relative bioavailability of (i) two 30 mg nifedipine gastro-intestinal therapeutic system (GITS) tablets (Adalat® XL, Bayer) administered once daily; (ii) one 60 mg nifedipine GITS tablet (Adalat® XL, Bayer) administered once daily; and (iii) one 20 mg plus one 10 mg nifedipine controlled-release tablet (Adalat® Retard, Bayer), administered 12 hourly. In both studies detailed pharmacokinetic data, in particular with respect to the controlled-release characteristics of the different formulations, were collected. Results of both studies indicate that all nifedipine products investigated are bioequivalent with respect to the extent of absorption of nifedipine. The nifedipine GITS products (Adalat® XL) have better controlled-release properties than the Adalat® Retard product, and are suitable for once-a-day administration.     

头孢他美酯分散片在人体内的相对生物利用度及生物等效性

目的建立HPLC法测定人血浆中头孢他美的浓度,并研究头孢他美酯分散片在人体内的相对生物利用度及生物等效性。方法18名受试者随机均分成两组,先后单剂量po受试制剂或参比制剂后,采用HPLC法测定血药浓度,计算药动学参数并进行生物等效性判定。结果单次服用0.5 g受试制剂或参比制剂后的药动学参数AUC0→14、AUC0→∞、Tm ax、Cm ax、t1/2分别为22.07±3.98μg.h.m l-1和21.31±4.37μg.h.m l-1,22.62±4.06μg.h.m l-1和21.99±4.54μg.h.m l-1,2.42±0.55 h和2.61±0.50 h,4.16±0.74μg.m l-1和3.95±0.87μg.m l-1,2.24±0.26 h和2.48±0.33 h。实验制剂对参比制剂的相对生物利用度为105.0%±14.6%。两种制剂的药动学参数无明显差异。结论受试制剂与参比制剂具有生物等效性。     

阿司匹林咀嚼片人体生物等效性研究

目的比较国产阿司匹林咀嚼片与水溶片剂的人体相对生物利用度。方法18名健康受试者进行随机交叉试验设计,分别先后单次口服324mg咀嚼片和300mg阿司匹林水溶片剂,采用高效液相色谱法测定血浆中阿司匹林浓度。结果咀嚼片与参比片剂的AUC0~t分别为(154.41±74.41)、(142.48±70.94)μgml-1h,Cmax分别为(25.83±6.04)、(25.07±5.72)μgml-1,Tmax分别为(0.81±0.33)、(0.79±0.41)h,T1/2分别为(3.43±1.02)、(3.25±1.21)h,供试品生物利用度为(101.09±13.56)%。结论药动学参数经方差分析双向单侧t检验无显著性差异,提示国产阿司匹林咀嚼片与水溶片剂具有生物等效性。     

双氯酚酸钾片人体生物等效性研究

目的评价双氯酚酸钾实验制剂和参比制剂的生物等效性。方法8名健康男性志愿者交叉单剂量口服双氯酚酸钾实验制剂或参比制剂50mg,采用反相高效液相色谱法测定经时过程血药浓度,血药浓度时间数据用3p97药代动力学实用程序拟合,计算其药代动力学参数。结果实验制剂和参比制剂主要药代动力学参数Ka分别为(3．042±1．356)h     

Pharmacokinetic evaluation of two different formulations of megestrol acetate in patients with advanced malignancies

The bioequivalence of two megestrol acetate formulations, 160-mg tablets and 160-mg sachets, was investigated in a single-dose, open-label, balanced-for-sequence cross-over study involving 12 advanced-cancer patients. The observed plasma megestrol-acetate time course obtained with both formulations was consistent with the literature data. The main source of variability in the pharmacokinetic parameters was intersubject variability; drug formulation played only a minor (and nonsignificant) role. The width of the 90% confidence interval of the areaunder-the-curve (AUC) ratio (sachets: tablets) computed according to Schuirmann (0.9–1.4) was mainly due to the presence of a single outlier, showing an AUC ratio of 2.7. The trend to higher bioavailability of the new formulation was not significant, especially as compared with the doseresponse data reported in the literature.     

奥美拉唑肠溶片生物利用度测定

目的　考察奥美拉唑肠溶片人体相对生物利用度及生物等效性。方法　 10名健康男性志愿者 ,采用交叉给药方案 ,分别单剂量po 2 0mg国产奥美拉唑肠溶片和进口奥美拉唑胶囊 ,用高效液相色谱紫外检测法测定血浆中奥美拉唑浓度 ,进行人体相对生物利用度和生物等效性评价。结果　单次po 2 0mg国产奥美拉唑肠溶片和进口奥美拉唑胶囊后 ,达峰时间tmax分别为 3 0 1± 0 5 2h和 2 6 2± 0 76h ;峰值血药浓度Cmax分别为 5 4 3 5± 2 14 9ng·ml-1和 5 2 0 9± 16 7 8ng·ml-1;药时曲线下面积AUC0→∞ 分别为 10 2 3 0± 5 4 2 5h·ng·ml-1和 10 71 2± 5 73 8h·ng·ml-1。结论　国产奥美拉唑肠溶片的相对生物利用度为96 4 0 % ,主要参数的双单侧t检验 ,结果显示两种制剂为生物等效制剂。     

非那雄胺片的人体生物等效性研究

目的:研究国产与进口非那雄胺片的人体生物等效性。方法:采用高效液相色谱法测定18名健康男性志愿者随机交叉单剂量口服非那雄胺片10mg后血清中的药物浓度,计算药动学参数和相对生物利用度,并进行生物等效性评价。结果:国产及进口非那雄胺片的AUC0～t 分别为(990 .80±302. 80)、(1007 .46±333. 65) (μg·h)/L ,Cmax 分别为(119. 22±18. 48)、(114. 08±22 .97) μg/L ,tmax 分别为(2. 89±1. 02)h、(2. 64±0. 54)h ,国产制剂相对于进口制剂的人体生物利用度为(103. 35±29 .75) %。结论:国产与进口非那雄胺片具有生物等效性。     

盐酸二甲双胍片人体生物等效性研究

目的 :研究盐酸二甲双胍片的人体生物等效性。方法 :20名健康男性志愿者单剂量随机、交叉口服盐酸二甲双胍参比制剂或受试制剂1000mg ,采用高效液相色谱法测定血浆中药物浓度。结果 :受试制剂和参比制剂的Cmax 分别为 (2 59±0 62)、(2 60±0 62) μg/ml,Tmax 分别为 (2 0±0 5)、(1 9±0 5)h ,T1/2 分别为 (3 01±0 54)、(2 90±0 50)h ,AUC0～12 分别为(13 21±3 28)、(12 99±2 98) (μg·h)/ml,AUC0～∞分别为 (14 29±3 44)、(13 91±3 23) (μg·h)/ml。受试制剂的相对生物利用度为 (101 6±7 9) %。结论 :受试制剂与参比制剂具有生物等效性。     

格列吡嗪胶囊的相对生物利用度和生物等效性

目的:考察格列吡嗪胶囊人体相对生物利用度及生物等效性。方法:20名健康男性志愿者,采用交叉给药方案,分别单剂量口服5.0mg受试格列吡嗪胶囊和参比格列吡嗪胶囊,用液相色谱-串联质谱法测定血浆中格列吡嗪浓度,进行人体相对生物利用度和生物等效性评价。结果:单次口服5.0mg受试格列吡嗪胶囊和参比格列吡嗪胶囊后,达峰时间(Tmax)分别为(2.1±0.5)h和(2.2±1.1)h;峰值血药浓度(Cmax)分别为(298.95±105.66)ng/ml和±281.55±68.84)ng/ml;半衰期(t1/2)分别为(4.14±1.33)h和(3.80±1.28)h;药时曲线下面积采用梯形法计算,AUC0-t分别为(1565.89±659.41)ng·h/ml和(1580.13±465.43)ng·h/ml,AUC0-∞分别为(1649.53±704.58)ng·h/ml和(1644.15±478.92)ng·h/ml。结论:受试格列吡嗪胶囊的相对生物利用度为(98.3±19.3)%,主要参数的双、单侧t检验,结果显示两种制剂为生物等效制剂。