XENICAL (orlistat) is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.
Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is:
Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pK a within the physiological pH range.
XENICAL is available for oral administration as a dark-blue or turquoise hard-gelatin capsule. The dark blue capsule is imprinted with light blue and the turquoise capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The dark blue capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No. 1 aluminum lake. The turquoise capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control. Systemic absorption of the drug is therefore not needed for activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Pharmacokinetics
Absorption
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-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 orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.
Metabolism
Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on an oral 14C-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 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 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 14C-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 14C-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, different races, patients with renal and hepatic insufficiency) were not conducted.
Pediatrics
Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.
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 orlistat.
Other Short-term Studies
Adults
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.
Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, XENICAL (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in orlistat and placebo treatment groups, respectively.
Dose-response Relationship
A simple maximum effect (Emax) 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.
CLINICAL STUDIES
Observational epidemiologic studies have established a relationship between obesity and visceral fat and the risks for cardiovascular disease, type 2 diabetes, certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for obese patients who have or are at risk of developing weight-related comorbidities. The long-term effects of orlistat on morbidity and mortality associated with obesity have not been established.
The effects of XENICAL on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of orlistat on weight regain. These studies included over 2800 patients treated with XENICAL and 1400 patients treated with placebo. The majority of these patients had obesity-related risk factors and comorbidities. In the XENDOS study, which included 3304 patients, the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with XENICAL and placebo designates treatment with XENICAL plus diet and placebo plus diet, respectively.
During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.
One-year Results: Weight Loss, Weight Maintenance, and Risk Factors
Weight loss was observed within 2 weeks of initiation of therapy and continued for 6 to 12 months.
Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 6 months and 1 year of treatment in the intent-to-treat population were 12.4 lbs and 13.4 lbs in the patients treated with XENICAL and 6.2 lbs and 5.8 lbs in the placebo-treated patients, respectively. During the 4-week placebo lead-in period of the studies, an additional 5 to 6 lb weight loss was also observed in the same patients. Of the patients who completed 1 year of treatment, 57% of the patients treated with XENICAL (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.
The percentages of patients achieving ≥ 5% and ≥ 10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in Table 1.
Table 1 Percentage of Patients Losing ≥ 5% and ≥ 10% of Body Weight From Randomization After 1-Year Treatment*
All studies, with the exception of 14161, were conducted at centers specialized in treating obesity and complications of obesity. Study 14161 was conducted with primary care physicians.
The relative changes in risk factors associated with obesity following 1 year of therapy with XENICAL and placebo are presented for the population as a whole and for the population with abnormal values at randomization.
Population as a Whole
The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in Table 2. One year of therapy with XENICAL resulted in relative improvement in several risk factors.
Table 2 Mean Change in Risk Factors From Randomization Following 1-Year Treatment* Population as a Whole
Population With Abnormal Risk Factors at Randomization
The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL ≥ 130 mg/dL, LDL/HDL ≥ 3.5, HDL <35 mg/dL) were greater for XENICAL compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the XENICAL group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP ≥ 140 mm Hg), the change in SBP from randomization to 1 year was greater for XENICAL (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure ≥ 90 mm Hg, XENICAL patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for XENICAL than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (≥ 120 pmol/L). A greater reduction in waist circumference for XENICAL vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (≥ 100 cm).
Effect on Weight Regain
Three studies were designed to eva luate the effects of XENICAL compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with XENICAL (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with XENICAL in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to eva luate the effects of 1 year of treatment with XENICAL on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.
In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with XENICAL regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with XENICAL regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with XENICAL regained 32% of the weight that they had lost (p<0.001).
Two-year Results: Long-term Weight Control and Risk Factors
The treatment effects of XENICAL were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see Table 1). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. XENICAL was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.
Pooled data from four clinical studies indicate that 40% of all patients treated with 120 mg three times a day of XENICAL and 24% of patients treated with placebo who completed 2 years of the same therapy had ≥ 5% loss of body weight from randomization. Pooled data from four clinical studies indicate that the relative weight loss advantage between XENICAL 120 mg three times a day and placebo treatment groups was the same after 2 years as for 1 year, indicating that the pharmacologic advantage of XENICAL was maintained over 2 years. In the same studies cited in the One-year Results (see Table 1), the percentages of patients achieving a ≥ 5% and ≥ 10% Weight Loss after 2 years are shown in Table 3.
Table 3 Percentage of Patients Losing ≥5% and ≥10% of Body Weight From Randomization After 2-Year Treatment*
All studies, with the exception of 14161 were conducted at centers specializing in treating obesity or complications of obesity. Study 14161 was conducted with primary care physicians.
The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.
Population as a Whole
The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.
Population With Abnormal Risk Factors at Randomization
The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.
Four-year Results: Long-term Weight Control and Risk Factors
In the 4-year double-blind, placebo-controlled XENDOS study, the effects of orlistat in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the orlistat group completed the 4-year study.
At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the orlistat group (p<0.001) (see Figure 1). Forty-five percent of the placebo patients and 73% of the orlistat patients lost ≥ 5% of their baseline body weight, and 21% of the placebo patients and 41% of the orlistat patients lost ≥ 10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the orlistat patients lost ≥ 5% of their baseline body weight and 10% of the placebo patients and 21% of the orlistat patients lost ≥ 10% of their baseline body weight.
Figure 1 Mean Change from Baseline Body Weight (Kgs) Over Time
The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see Table 4).
Table 4 Mean Change in Risk Factors From Randomization Following 4-Years Treatment*
