生物等效性试验中受试者食用高脂餐的调查研究

目的评价餐后生物等效性试验中受试者食用高脂餐的情况,总结高脂餐食谱制订的考虑因素。方法对完成首都医科大学附属北京朝阳医院Ⅰ期临床试验研究室(以下简称"本中心")两周期、双交叉、餐后生物等效性试验的33例健康受试者的高脂餐食谱、就餐时间、进食量进行分析,对食用西式高脂餐的21例受试者进行就餐感受的问卷调查,调查内容包括食用高脂餐的感受、餐后饱腹感、餐后有无不适、对于中西式高脂餐的选择和对西式高脂餐中接受度不高的成分。结果本中心选择的中式、西式高脂餐对于受试者的进食量均无影响;57. 14%的受试者倾向于食用西式高脂餐,42. 86%的受试者倾向于食用中式高脂餐;西式高脂餐中接受度不高的成分主要有黄油(33. 33%)、纯牛奶(14. 29%)、沙拉酱(14. 29%)、美式培根(9. 52%)。结论本中心选择的中西式高脂餐基本满足试验需要。综合考虑指导原则要求、受试者就餐感受、避免接受度不高的食物成分等因素,制订更为合理的高脂餐食谱,从而提高临床试验质量。     

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet

Abstract

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5?mg VNP composed of Maisine? 35-1, Transcutol^® HP, and Cremophor^® EL was adsorbed on the solid carrier Aeroperl^®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel^®, HPMC-K4M, PVP-K30, and Lubripharm^®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 3²*2¹ full factorial design was adopted. The independent variables were: type of coating material (X₁), concentration of coating solution (X₂), and number of drills (X₃). The dependent variables included % release at 2?h (Y₁), at 4?h (Y₂), and at 8?h (Y₃). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry^® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.     

Comparing two botulinum toxin type A formulations using manufacturers' product summaries

Background and objective: Because of the unique pharmacology and clinical versatility of botulinum toxin (BoNT), particularly BoNT serotype A (BoNTA), a need exists for discussion of the current data on similarities and differences between two BoNTA products, BOTOX and Dysport. Methods: We compared the physiochemical and pharmacological properties of BOTOX and Dysport using information from the Summary of Product Characteristics (SmPC) documents from a number of countries around the world. Results and discussion: Our analysis based on the SmPC documents demonstrated distinct differences in physical characteristics, breadth of approved indications, dosing and administration, and the incidence and severity of adverse events. Conclusion: BOTOX and Dysport are not bioequivalent. Many of the differences between BOTOX and Dysport discussed within are probably related to the differences in their physical characteristics.     

布洛芬缓释胶囊单剂量与多剂量给药的人体药动学及生物等效性研究

目的：建立高效液相色谱法测定人血浆中布洛芬浓度,并应用于两种布洛芬缓释制剂的人体生物等效性研究。方法：采用双周期自身随机交叉试验设计,24名男性健康志愿者分别单剂量、多剂量口服布洛芬缓释胶囊受试制剂和参比制剂300mg,采用高效液相色谱法测定人血浆中布洛芬浓度,利用DAS 2.0程序计算主要药动学参数,并对两种制剂进行生物等效性评价。结果：单剂量口服受试制剂和参比制剂后血浆中布洛芬的Cmax分别为（12.7±5.4）和（13.5±5.9）μg/mL,tmax分别为（5.5±1.4）和（5.1±1.0）h,AUC0→24分别为（96.8±50.2）和（95.7±45.4）μg·h·mL^-1。多剂量口服受试制剂和参比制剂后血浆中布洛芬的Cmax分别为（14.1±5.3）和（14.9±6.4）μg/mL,tmax分别为（4.8±1.0）和（4.6±0.9）h,Cav分别为（8.3±3.4）和（8.6±4.3）μg/mL,DF值分别为（117.2±35.3）%和（131.7±35.1）%。经统计学检验,两种制剂主要药动学参数间无统计学差异（P〉0.05）。结论：所建立的高效液相色谱法适合用于人体血浆中布洛芬测定。布洛芬受试制剂和参比制剂具有生物等效性。     

谷氨酰胺胶囊在健康人体的生物等效性研究

目的：研究中国健康受试者单次口服谷氨酰胺胶囊的人体生物等效性。方法将36名男性健康受试者随机分为2组,分别单剂量口服试验药或参比药4.0 g,洗脱1周后,交叉给药,用高效液相色谱与二级质谱联用（ HPLC－MS／MS）方法测定血药浓度,计算两者的主要药代动力学参数和相对生物利用度。结果口服试验药和参比药后,血浆中谷氨酰胺主要药动学参数如下：tmax分别为（0.69±0.66）和（0.66±0.33） h,Cmax分别为（127.80±53.48）和（123.10±40.42）μg · mL－1,以 AUC0→∞计算,试验药相对生物利用度为（99.96±39.92）％。结论试验药与参比药在健康受试者体内生物作用等效。     

人体生物等效性试验中生物样品分析的关键问题研究

采用体内生物等效性试验的方法开展一致性评价是仿制药申请的基础,生物等效性试验首选药动学研究的方法,而药动学中生物样品分析是最为重要的环节,它将直接影响药品的安全性和有效性,为生物等效性试验的结果做出关键性决定。目前我国的生物样品分析质量还有很大提升空间,基于此,本文根据相关指导原则,结合工作实际,针对生物等效性试验中生物样品分析方法的建立、验证、测试、记录和注意事项等,探讨生物等效性试验中生物样品分析的关键问题。     

应用生理药动学模型评估雷尼替丁片剂生物等效豁免的影响因素

目的：建立雷尼替丁片剂在健康人体内的生理药动学（PBPK）模型,并用该模型模拟各因素对盐酸雷尼替丁片剂生物等效性的影响,为生物等效豁免标准的制定提供参考。方法：查询不同数据库关于雷尼替丁理化参数的相关文献,遵照美国食品与药物监督管理局（FDA）的生物等效研究的指导原则,采用GastroPlus^TM9.5软件建立雷尼替丁注射给药和口服给药的PBPK模型,并通过倍数误差来评价模型的有效性;再根据已建立的PBPK模型对可能影响雷尼替丁片剂生物等效性的各因素进行体内模拟。结果：PBPK模型预测雷尼替丁的药-时曲线与实测值拟合良好。药动学参数最大血药浓度（C_max）、达峰时间（t_max）、血药浓度-时间曲线下总面积（AUC_0-inf）和截止至终末观察点时的血浆药物浓度-时间曲线下面积（AUC_0-t）与实测值接近,倍数误差 < 2。影响因素沉淀时间（90~9 000 s）、胃pH（0.5~6）、十二指肠pH（0.5~8）、溶解度（100~10 000 g·L^-1）对C_max和AUC_0-t值几乎无影响;当胃排空时间在0.125~0.5 h内时,随着胃排空时间延长,C_max略有下降,AUC_0-t基本不变,C_max和AUC_0-t均符合生物等效（BE）标准;当渗透性在（0.62~2.48）×10^-4 cm·s^-1内时,随着渗透性增加,C_max和AUC_0-t均增加;C_max在渗透性为（0.84~1.82×10^-4 ）cm·s^-1时符合BE标准,在渗透性研究范围之内AUC_0-t均符合BE标准;当小肠转运时间在1.586~6.344 h内时,随着小肠转运时间增加,C_max略有增加,AUC_0-t也略有增加,C_max和AUC_0-t都符合BE标准;在120 min内药物溶出度达到85%时,不同制剂与口服溶液在体内的C_max和AUC_0-t是一致的,不会受溶出的影响。结论：所建PBPK模型准确可靠,可用于模拟和评价各因素对BE试验的影响程度,为生物等效豁免标准的制定提供参考。     

An approximate approach to sample size determination in bioequivalence testing with multiple pharmacokinetic responses

The approval of generic drugs requires the evidence of average bioequivalence (ABE) on both the area under the concentration–time curve and the peak concentration C_max. The bioequivalence (BE) hypothesis can be decomposed into the non‐inferiority (NI) and non‐superiority (NS) hypothesis. Most of regulatory agencies employ the two one‐sided tests (TOST) procedure to test ABE between two formulations. As it is based on the intersection–union principle, the TOST procedure is conservative in terms of the type I error rate. However, the type II error rate is the sum of the type II error rates with respect to each null hypothesis of NI and NS hypotheses. When the difference in population means between two treatments is not 0, no close‐form solution for the sample size for the BE hypothesis is available. Current methods provide the sample sizes with either insufficient power or unnecessarily excessive power. We suggest an approximate method for sample size determination, which can also provide the type II rate for each of NI and NS hypotheses. In addition, the proposed method is flexible to allow extension from one pharmacokinetic (PK) response to determination of the sample size required for multiple PK responses. We report the results of a numerical study. An R code is provided to calculate the sample size for BE testing based on the proposed methods. Copyright © 2014 John Wiley & Sons, Ltd.