Xenical Clinical Pharmacology

Pharmacokinetics:    Absorption: Systemic exposure to Xenical is minimal. Following oral dosing with 360 mg ¹⁴ C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.

The average absolute bioavailability of intact orlistat was assessed in studies with male rats at oral doses of 150 and 1000 mg/kg/day and in male dogs at oral doses of 100 and 1000 mg/kg/day and found to be 0.12%, 0.59% in rats and 0.7%, 1.9% in dogs, respectively.

Distribution:   In vitro Xenical was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Xenical minimally partitioned into erythrocytes.

Metabolism:    Based on animal data, it is likely that the metabolism of Xenical occurs mainly within the gastrointestinal wall. Based on an oral ¹⁴ C-orlistat mass balance study in obese patients, two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open (beta)-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 the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

Elimination:   Following a single oral dose of 360 mg ¹⁴ C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg ¹⁴ C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.

Special Populations:   Because the drug is minimally absorbed, studies in special populations (geriatric, pediatric, different races, patients with renal and hepatic insufficiency) were not conducted.

Drug-Drug Interactions:   Drug-drug interaction studies indicate that Xenical had no effect on pharmacokinetics and/or pharmacodynamics of alcohol, digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives, phenytoin, pravastatin or warfarin. Alcohol did not affect the pharmacodynamics of Xenical.

Other Short-term Studies:   In several studies of up to 6-weeks duration, the effects of therapeutic doses of Xenical on gastrointestinal and systemic physiological processes were assessed in normal-weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of Xenical in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of Xenical in these studies. In a 3-week study of 28 healthy male volunteers, Xenical (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.

Dose-response Relationship:   A simple maximum effect (E _max ) model was used to define the dose-response curve of the relationship between Xenical daily dose and fecal fat excretion as representative of gastrointestinal lipase inhibition. The dose-response curve demonstrated a steep portion for doses up to approximately 400 mg daily, followed by a plateau for higher doses. At doses greater than 120 mg three times a day, the percentage increase in effect was minimal.