Efficacy in Patients with Type 2 Diabetes: Pooled data from four 1-year studies and three 6-month studies in type 2 diabetic patients showed that the percentage of responders (≥10% of body weight loss) was 11.3% with orlistat as compared to 4.5% with placebo. The mean difference in weight loss with the drug compared to placebo was 2.47 kg in these patients.
The pooled data from the four 1-year studies and three 6-month studies of Xenical as an adjunct to antidiabetic medications are summarized in the following table: See table.
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Pharmacokinetics: Absorption: Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were nonmeasurable (<5 ng/mL) 8 hrs following oral administration of orlistat.
In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 micromole), without evidence of accumulation, and consistent with negligible absorption.
Distribution: The volume of distribution cannot be determined because the drug is minimally absorbed and has no defined systemic pharmacokinetics. In vitro, orlistat is >99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.
Metabolism: Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a study in obese patients, of the minute fraction of the dose that was absorbed systemically, 2 major metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1, with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasma concentration.
M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 and 108 ng/mL, respectively), these metabolites are considered to be pharmacologically inconsequential.
Elimination: Studies in normal weight and obese subjects have shown that fecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of the administered dose was excreted in feces and 83% of that as unchanged orlistat.
The cumulative renal excretion of total orlistat-related materials was <2% of the given dose. The time to reach complete excretion (fecal plus urinary) was 3-5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.