Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
Pharmaco-therapeutic group: Peripherally acting antiobesity agent
ATC code: A08AB01
Orlistat is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unavailable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides.
In the 2-year studies and the 4-year study, a hypocaloric diet was used in association with treatment in both the orlistat and the placebo treated groups.
Pooled data from five 2 year studies with orlistat and a hypocaloric diet showed that 37% of orlistat patients and 19% of placebo patients demonstrated a loss of at least 5% of their baseline body weight after 12 weeks of treatment. Of these, 49% of orlistat treated patients and 40% of placebo treated patients went on to lose ≥10% of their baseline body weight at one year. Conversely, of patients failing to demonstrate a loss of 5% of their baseline body weight after 12 weeks of treatment, only 5% of orlistat treated patients and 2% of placebo treated patients went on to lose ≥10% of their baseline body weight at one year. Overall, after one year of treatment, the percentage of patients taking 120 mg orlistat who lost 10% or more of their body weight was 20% with orlistat 120 mg compared to 8% of patients taking placebo. The mean difference in weight loss with the drug compared to placebo was 3.2 kg.
Data from the 4-year XENDOS clinical trial showed that 60% of orlistat patients and 35% of placebo patients demonstrated a loss of at least 5% of their baseline body weight after 12 weeks of treatment. Of these, 62% of orlistat treated patients and 52% of placebo treated patients went on to lose ≥10% of their baseline body weight at one year. Conversely, of patients failing to demonstrate a loss of 5% of their baseline body weight after 12 weeks of treatment, only 5% of orlistat treated patients and 4% of placebo treated patients went on to lose ≥10% of their baseline body weight at one year. After 1 year of treatment, 41% of the orlistat treated patients versus 21% of placebo treated patients lost
More patients on orlistat or placebo lost baseline body weight of at least 5% at 12 weeks or 10% at one year in the XENDOS study than in the five 2-year studies. The reason for this difference is that the five 2-year studies included a 4-week diet and placebo lead-in period during which patients lost on average 2.6 kg prior to commencing treatment.
Data from the 4-year clinical trial also suggested that weight loss achieved with orlistat delayed the development of type 2 diabetes during the study (cumulative diabetes cases incidences: 3.4% in the orlistat group compared to 5.4% in the placebo-treated group). The great majority of diabetes cases came from the subgroup of patients with impaired glucose tolerance at baseline, which represented 21% of the randomised patients. It is not known whether these findings translate into long-term clinical benefits.
In obese type 2 diabetic patients insufficiently controlled by antidiabetic agents, data from four one- year clinical trials showed that the percentage of responders (>10% of body weight loss) was 11.3% with orlistat as compared to 4.5% with placebo. In orlistat-treated patients, the mean difference from placebo in weight loss was 1.83 kg to 3.06 kg and the mean difference from placebo in HbA1c reduction was 0.18% to 0.55%. It has not been demonstrated that the effect on HbA1c is independent from weight reduction.
In a multi-centre (US, Canada), parallel-group, double-blind, placebo-controlled study, 539 obese adolescent patients were randomised to receive either 120 mg orlistat (n=357) or placebo (n=182) three times daily as an adjunct to a hypocaloric diet and exercise for 52 weeks. Both populations received multivitamin supplements. The primary endpoint was the change in body mass index (BMI) from baseline to the end of the study.
The results were significantly superior in the orlistat group (difference in BMI of 0.86 kg/m² in favour of orlistat). 9.5% of the orlistat treated patients versus 3.3% of the placebo treated patients lost ≥10% of body weight after 1 year with a mean difference of 2.6 kg between the two groups. The difference was driven by the outcome in the group of patients with >5% weight loss after 12 weeks of treatment with orlistat representing 19% of the initial population. The side effects were generally similar to those observed in adults. However, there was an unexplained increase in the incidence of bone fractures (6% versus 2.8% in the orlistat and placebo groups, respectively).
Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were non-measurable (<5 ng/ml) eight hours 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 μmol), with no evidence of accumulation, which is consistent with minimal absorption.
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.
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 minimal fraction of the dose that was absorbed systemically, two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasma concentration.
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 therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites are considered to be pharmacologically inconsequential.
Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces 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 (faecal plus urinary) was 3 to 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.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogenic effect in animals, no malformative effect is expected in man. To date, active substances responsible for malformations in man have been found teratogenic in animals when well-conducted studies were performed in two species.
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