奥利司他60mg胶囊的药效学等效性。一项开放标签、平衡、随机、多剂量、交叉药效学终点生物等效性研究,在健康、成人、亚洲印第安人受试者中进行

Sudershan Kumar, T. Monif, R. Arora, A. Khuroo, Rakesh K. Jain, S. Reyar, P. Verma, Shireen Rao
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引用次数: 3

摘要

奥利司他是一种治疗肥胖的非全身药物。该药物通过与胃和胰腺脂肪酶的活性位点可逆结合,抑制胃肠道中的脂肪酶,主要在胃和小肠的管腔中,阻止约30-35%的膳食脂肪的吸收。未消化的甘油三酯不能被吸收,导致热量不足,对控制体重有积极作用。本研究的目的是利用药效学终点评估奥利司他作为通用和参考胶囊制剂的生物等效性。总共有60名健康志愿者参加了为期5天的饮食磨合期,以适应低脂肪饮食;然后,受试者随机接受奥利司他(60mg)口服剂量,每日3次,连续10天,作为仿制(Ranbaxy实验室)或参考(Alli™,葛兰素史克)胶囊配方。在整个研究中,受试者遵循标准化饮食(2500千卡/天,约30%为脂肪)。在磨合期的最后2天(基线)和两个治疗期的最后5天收集粪便。采用经验证的FTIR方法测定饲料和粪便中的脂肪量,检测限分别为1.00 g%。24小时的粪便脂肪排泄量(FFE24SS,根据摄入脂肪量调整的粪便脂肪排泄量计算)作为药效学终点,评估两种奥利司他制剂之间的生物等效性。对对数变换后的FFE24SS参数进行方差分析(ANOVA),以确定仿制药相对于创新制剂的生物等效性。奥利司他仿制剂型和创新剂型在基线和重复口服后的平均FFE24SS值分别为0.88%、40.55%和40.54%。仿制药与创新制剂FFE24SS的最小二乘均值(LSM)为101.90%,90%置信区间为97.94 ~ 106.01%。在两期研究中,受试者对奥利司他的耐受性良好,在研究期间未观察到严重的不良事件。综上所述,平均FFE24SS值被用作药效学终点来评估两种奥利司他制剂之间的生物等效性。本研究的结果表明,奥利司他胶囊的试验配方在喂养条件下以多剂量给药给健康志愿者时,与参考市场上的Alli™具有生物等效性。
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The pharmacodynamic equivalence of Orlistat 60 mg capsule. An open label, balanced, randomized, multiple-dose, cross-over pharmacodynamic end-point bioequivalence study in healthy, adult, human Asian Indian subjects under fed conditions
Abstract Orlistat is a non-systemic treatment for obesity. The drug inhibits lipase in the gastrointestinal track mainly in the lumen of the stomach and small intestine by binding reversibly with the active site of gastric and pancreatic lipases, preventing the absorption of ∼30–35% of dietary fat. The undigested triglycerides are not absorbed, resulting in a caloric deficit and positive effect in weight control. The objective of this study was to assess the bioequivalence of orlistat administered as a generic and reference capsule formulations using a pharmacodynamic end-point. A total of 60 healthy volunteers followed a 5-day run-in diet period to be accustomed to a low fat diet; subjects were then randomized to receive under fed conditions oral doses of orlistat (60 mg) 3-times daily for 10 days as the generic (Ranbaxy Laboratories) or reference (Alli™, GlaxoSmithKline) capsule formulations. Subjects followed a standardized diet (2500 kcal/day, ∼30% as fat) for the entire study. Feces were collected over the last 2 days of the run-in period (baseline) and over the last 5 days of the two treatment periods. The amount of fat in meals and feces were assayed using the validated FTIR method with a limit of detection of 1.00 g%, respectively. Fecal fat excretion over 24 h (FFE24SS, calculated as the amount of fat excreted in feces adjusted by the amount of fat ingested) was used as a pharmacodynamic end-point to assess the bioequivalence between the two orlistat formulations. An analyses of variance (ANOVA) was performed on the log-transformed FFE24SS parameter to establish bioequivalence of the generic product with respect to the innovator formulation. Mean FFE24SS values at baseline and after repeated oral administrations of the generic and innovator formulations of orlistat were 0.88%, 40.55% and 40.54%, respectively. The ratio of least-squares means (LSM) of FFE24SS of the generic to the innovator formulation was 101.90%, with 90% confidence intervals of 97.94–106.01%. Orlistat was well tolerated by subjects in both periods of study and no serious adverse events were observed during the study. In conclusion, mean FFE24SS values were used as pharmacodynamic end-points to assess bioequivalence between two formulations of orlistat. Results from this study suggest that the test formulation of Orlistat capsule is bioequivalent to the reference marketed Alli™ when administered to healthy volunteers as a multiple dose under fed conditions.
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