Pharmacodynamic equivalence of two orlistat capsule formulations in healthy volunteers under fed conditions.

摘要

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.