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121.
PURPOSE: i) To develop novel approaches for the construction of bioequivalence (BE) limits incorporating both the intrasubject variability and the geometric mean ratio (GMR), and ii) to assess the performance of the novel approaches in comparison to several scaled BE procedures and the classic unscaled average BE. METHODS: Plots of the BE limits or the extreme GMR values accepted as a function of the coefficient of variation (CV) were constructed for published and the developed scaled procedures. Two-period crossover BE investigations with 12, 24, or 36 subjects were simulated with assumptions of a CV 10%, 20%, 30%, or 40%. The decline in the percentage of accepted studies was recorded as the true GMR for the two formulations was raised from 1.00 to 1.50. Acceptance of BE was evaluated by published and the developed scaled procedures, and, for comparison, by the unscaled average BE. RESULTS: Two GMR-dependent BE limits are proposed for the evaluation of average BE: i) BELscG1 with Ln(Upper, Lower BE limit) = +/-[(5 - 4GMR)0.496s + Ln(1.25)], and ii) BELscG2 with Ln(Upper, Lower BE limit) = +/-[(3 - 2GMR)(0.496s + Ln(1.25))], where s is the square root of the intrasubject variance. The range of BE limits becomes narrower as GMR values deviate from unity, and increases with variability. The two new approaches exhibit the highest statistical power at low CV values. At high levels of variability, BELscG1 and BELscG2 show high statistical power, as well as the lowest percentages of acceptance among the scaled methods when GMR = 1.25. The latter becomes more obvious when a large number of subjects is incorporated in the studies. CONCLUSIONS: The GMR and CV estimates of the BE study can be used in conjunction with the GMR vs. CV plot for the assessment of average BE. The new approaches, BELscG1 and BELscG2, appear to be highly effective at all levels of variation investigated. 相似文献
122.
Najib NM Idkaidek N Adel A Admour I Astigarraga RE Nucci GD Alam SM Dham R Qumaruzaman 《Biopharmaceutics & drug disposition》2003,24(5):183-189
The pharmacokinetics of two brands of simvastatin 40 mg tablets were compared in 24 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at IPRC, Amman, Jordan. Reference (Zocor, MSD, Netherlands) and test (Simvast, Julphar, UAE) products were administered to fasted volunteers; blood samples were collected at specified time intervals, plasma separated and analyzed for simvastatin and its active metabolite (beta-hydoxy acid) using a validated LC-MS/MS method at Cartesius Analytical Unit, Institute of Biomedical Sciences - USP, Sao Paulo, Brazil. The pharmacokinetic parameters AUC(0-t), AUC(0-variant), C(MAX), T(MAX), T(1/2) and elimination rate constant were determined from plasma concentration-time profile for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Simvast is bioequivalent to Zocor of MSD, Netherlands. 相似文献
123.
Influence of a Microemulsion Vehicle on Cutaneous Bioequivalence of a Lipophilic Model Drug Assessed by Microdialysis and Pharmacodynamics 总被引:9,自引:0,他引:9
Kreilgaard M Kemme MJ Burggraaf J Schoemaker RC Cohen AF 《Pharmaceutical research》2001,18(5):593-599
Purpose. The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil–in–water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method.
Methods. Dermal delivery of lidocaine was estimated by microdialysis in 8 volunteers. Absorption coefficients and lag times were determined by pharmacokinetic modelling of the microdialysis data. Subsequently, the anaesthetic effect of the treatments was assessed by mechanical stimuli using von Frey hairs in 12 volunteers.
Results. The microemulsion formulation increased the cutaneous absorption coefficient of lidocaine 2.9 times (95% confidence interval: 1.9/4.6) compared with the O/W emulsion–based cream. Also, lag time decreased from 110 ± 43 min to 87 ± 32 min (P = 0.02). The compartmental pharmacokinetic model provided an excellent fit of the concentration–time curves with reliable estimation of absorption coefficient and lag time. A significant anaesthetic effect was found for both active treatments compared to placebo (P < 0.02), but the effect did not diverge significantly between the two formulations.
Conclusions. The microemulsion vehicle can be applied to increase dermal drug delivery of lipophilic drugs in humans. The microdialysis technique combined with an appropriate pharmacokinetic model provides a high sensitivity in bioequivalence studies of topically applied substances. 相似文献
124.
Subject-by-Formulation Interaction in Determinations of Individual Bioequivalence: Bias and Prevalence 总被引:1,自引:0,他引:1
Purpose. 1. To determine properties of the estimated variance component for the subject-by-formulation interaction (2
D) in investigations of individual bioequivalence (IBE), and 2. to evaluate the prevalence of interactions in replicate-design studies published by FDA.
Methods. Four-period crossover studies evaluating IBE were simulated repeatedly. Generally, the true bioequivalence of the two formulations, including 2
D= 0, was assumed, 2
D was then estimated in a linear mixed-effect model by restricted maximum likelihood (REML). The same method was applied for estimating 2
D for the data sets of FDA.
Results. 1.D estimated by REML was positively biased. The bias and dispersion of the estimated Dincreased approximately linearly with the estimated within-subject standard deviation for the reference formulation (WR). Only a small proportion of the estimated D exceeded the estimated WR. 2. Distributions of the estimated D were evaluated. At WR = 0.30, a level of estimated D= 0.15 was exceeded, by random chance, with a probability of about 25%. 3. Importantly, the behaviour of the 2
D values estimated from the FDA data sets was similar to that exhibited by the simulated estimates of 2
D which were generated under the conditions of true bioequivalence.
Conclusions. 1. D estimated by REML is biased; the bias increases proportionately with the estimated WR. Consequently, exceeding a fixed level of D (e.g., 0.15) does not indicate substantial interaction. 2. The data sets of FDA are compatible with the hypothesis of 2
D = 0. Consequently, they do not demonstrate the prevalence of subject-by-formulation interaction. Therefore, it could be sufficient and reasonable to evaluate bioequivalence from 2-period crossover studies. 相似文献
125.
Al-Said MS Al-Khamis KI Niazy EM El-Sayed YM Al-Rashood KA Al-Bella S Al-Yamani MA Al-Najjar TA Alam SM Dham R Zaman Qumaruzaman Q 《Biopharmaceutics & drug disposition》2000,21(6):205-210
A bioequivalence study of two oral formulations of 500 mg cefuroxime axetil was carried out in 24 healthy volunteers following a single dose, standard two-treatment cross-over design at the College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, working jointly with King Khalid University Hospital. The two formulations used were Cefuzime (Julphar, United Arab Emirates) as the test and Zinnat (Glaxo Wellcome, England) as the reference product. Both test and reference tablets were administered to each subject after an overnight fasting on two treatment days separated by a 1-week washout period. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analysed for cefuroxime by a sensitive, reproducible and accurate high pressure liquid chromatography (HPLC) method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2) and K(el) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on an analysis of variance (ANOVA); 90% confidence interval for test/reference ratio of these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Cefuzime is bioequivalent to Zinnat. 相似文献
126.
William Pomerance 《Postgraduate medicine》2013,125(2):42-50
The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. 相似文献
127.
《Clinical Research and Regulatory Affairs》2013,30(2):32-41
Evidence of differences in bioavailability from different oral formulations of the same therapeutic agents had become obvious by the early 1960s. The consequent 40 years have produced the body of scientific belief, debate, and policy on the subject of bioequivalence. The motivating force behind many of these events has been the continued interest of the food and drug administration (FDA) to improve the manner in which these studies are conducted, the quality of the data generated from such studies, and the methods by which they are evaluated. Bioanalytical data used to support regulatory submission needs to be accurate and reproducible. In order to have confidence in the reliability of the data, it is important that the analytical method used to generate it is well characterized and fully validated. However, bioavailability assessment (BA) and bioequivalence (BE) studies are necessary in filing of the data towards the drug approval. This review article describes the methods for assessing bioavailability and bioequivalence; and bioanalytical approaches of pharmaceuticals in vivo and in vitro and also a waiver of BA/BE studies based on the biopharmaceutical classification (BCS) system. 相似文献
128.
Higuinaldo J. Chaves Das Neves Marco D.R. Gomes da Silva M.P. Rocha 《Journal of pharmaceutical and biomedical analysis》1991,9(10-12):941-947
A solid-phase extraction technique for sample clean-up coupled with a new LC procedure is reported for the assay of diltiazem in plasma. The use of disposable cartridges provides selective extraction and easy automation. A new LC system based on LiChrospher RP 60 Select B columns is described. For routine analysis, the procedure provides a rapid simultaneous clean-up of several samples prior to chromatography and reproducible recoveries over a concentration range of 10-800 ng. The procedure was used to analyse the plasma samples from a bioequivalence study of three commercial diltiazem preparations. The pharmacokinetic parameters in 12 healthy male volunteers were determined and the assessment of bioequivalence was conducted by discriminant analysis. 相似文献
129.
目的 :比较国产与进口两种盐酸西替利嗪片剂在健康成年男性志愿者体内的药代动力学和生物利用度。方法 :12名健康志愿者采用2周期随机交叉设计自身对照试验法 ,口服进口与国产盐酸西替利嗪片各10mg ,以反相高效液相色谱法测定血浆中药物浓度。结果 :国产西替利嗪与进口西替利嗪的主要药代动力学参数如下 :Cmax 分别为 (429 00±108 80)ng/ml和 (469 82±113 83)ng/ml,Tmax 分别为 (0 90±0 51)h和 (0 91±0 40)h ,以梯形法计算AUC0~36 分别为 (3312 72±682 39)ng/(ml·h)和 (3417 11±517 42)ng/(ml·h)。国产西替利嗪相对生物利用度为 (97 21±13 32) %。主要药代动力学参数经方差分析和双单侧t检验证明 ,无显著性差异 (P>0 05)。结论 :国产西替利嗪与进口西替利嗪在受试者体内的药代动力学参数相似 ,具有生物等效性 相似文献
130.
三种头孢克洛胶囊的生物等效性研究 总被引:8,自引:1,他引:7
以盐野义制药株式会社的头孢克洛缓释胶囊 (B)和 L illy公司的头孢克洛普通胶囊 (C)为参比制剂 ,在 12名男性健康受试者中对国产头孢克洛缓释胶囊 (A)进行了生物等效性及药物动力学研究。采用反相高效液相色谱 -紫外检测法测定血浆中头孢克洛浓度。 A、B、C三种胶囊的 AUC0→ tn分别为 2 3.87± 4 .11、2 2 .5 3± 4 .37、2 4 .14± 2 .87μg· ml- 1 · h,A与 B各参数均无显著性差异 ,与 C相比 ,Cmax明显降低 ,血浆浓度维持 MIC以上时间延长 1.83倍 ,具有显著的缓释特性 相似文献