Di Marco M, Marier J F, Ducharme M P, Morin I, Engel C, Gulbranson S, Thudi N R, Murpani D, Rampal A, Monif T, Koundinya T S, Deo K, Monif T
MDS Pharma Services, St.-Laurent (Montréal), Québec, QC, Canada.
Int J Clin Pharmacol Ther. 2008 Jun;46(6):319-26. doi: 10.5414/cpp46319.
Orlistat is a reversible lipase inhibitor for obesity management. Orlistat exerts its pharmacological activity in the lumen of the stomach and small intestine by binding with the active site of gastric and pancreatic lipases, with the consequent inhibition of the systemic absorption of dietary fat. The undigested triglycerides are not absorbed, resulting in caloric deficit and positive effect in weight control. The objective of this study was to assess, using fat excreted in feces, the pharmacodynamic equivalence of orlistat when administered as generic and innovator capsule formulations.
A total of 18 healthy volunteers (12 males and 6 females) followed a 5-day run-in diet period in order to become accustomed to a high fat diet. Subjects were then randomized to receive under fed conditions oral doses of orlistat (120 mg) 3 times daily for 10 consecutive days as the generic (Ranbaxy Laboratories) or innovator (Xenical, Roche Laboratories, Nutley, NJ, USA) capsule formulations. Subjects followed a standardized diet (2,500 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 2 treatment periods. The amount of fat in meals and feces was assayed with a limit of detection of 0.1 and 0.2%, respectively. Fecal fat excretion over 24 hours (FFE(24), calculated as the percentage of amount of fat excreted in feces relative to the amount of fat ingested) was used as a pharmacodynamic endpoint to assess the therapeutic equivalence between the 2 orlistat formulations. An analysis of variance (ANOVA) was performed on FFE(24) parameters.
Mean FFE(24) values at baseline and after repeated oral administrations of the generic and innovator formulations of orlistat were 6.48, 20.0 and 19.6%, respectively. The ratio of least-squares means (LSM) of FFE(24) of the generic to the innovator formulation was 99.1%, with 90% confidence intervals of 83.8 -114.5%. Adverse events for the generic and innovator products were similar in nature and frequency.
Mean FFE(24) values were used as pharmacodynamic endpoints to assess equivalence between 2 formulations of orlistat. Results from this study suggest that pharmacodynamics of the generic capsule formulation of orlistat were similar to the marketed capsule formulation based on FFE(24) values.
奥利司他是一种用于肥胖管理的可逆性脂肪酶抑制剂。奥利司他通过与胃和胰脂肪酶的活性位点结合，在胃和小肠腔内发挥其药理活性，从而抑制膳食脂肪的全身吸收。未消化的甘油三酯不被吸收，导致热量不足并对体重控制产生积极作用。本研究的目的是通过检测粪便中排出的脂肪，评估奥利司他通用胶囊制剂和创新胶囊制剂给药时的药效学等效性。
总共18名健康志愿者（12名男性和6名女性）进行了为期5天的适应期饮食，以便适应高脂肪饮食。然后，受试者被随机分组，在进食不足的条件下，连续10天每天口服3次奥利司他（120毫克），分别使用通用制剂（兰伯西实验室）或创新制剂（赛尼可，罗氏实验室，美国新泽西州纳特利）胶囊。在整个研究过程中，受试者遵循标准化饮食（2500千卡/天，30%为脂肪）。在适应期的最后2天（基线）以及2个治疗期的最后5天收集粪便。测定膳食和粪便中的脂肪量，检测限分别为0.1%和0.2%。24小时粪便脂肪排泄量（FFE(24)，计算为粪便中排出的脂肪量相对于摄入的脂肪量的百分比）用作药效学终点，以评估两种奥利司他制剂之间的治疗等效性。对FFE(24)参数进行方差分析（ANOVA）。
奥利司他通用制剂和创新制剂在基线和重复口服给药后的平均FFE(24)值分别为6.48%、20.0%和19.6%。通用制剂与创新制剂的FFE(24)最小二乘均值（LSM）之比为99.1%，90%置信区间为83.8 - 114.5%。通用产品和创新产品的不良事件在性质和频率上相似。
平均FFE(24)值用作药效学终点来评估两种奥利司他制剂之间的等效性。本研究结果表明，基于FFE(24)值，奥利司他通用胶囊制剂的药效学与市售胶囊制剂相似。
