Description:
Orlistat is a gastrointestinal lipase inhibitor
indicated for obesity management, including weight loss and weight maintenance,
when used in conjunction with a reduced-calorie diet.
The first in a new class
of drugs, orlistat works non-systemically to block the absorption of dietary
fat. Even though orlistat was placed on a fast-track by the FDA, final approval
was delayed when results of clinical trials suggested a higher incidence of
breast cancer in the orlistat group compared to placebo.
Based on orlistat's minimal
systemic absorption, lack of an estrogen-stimulating effect in women, and
evidence of tumor preexistence at randomization, investigators concluded that
no biological association between orlistat and breast cancer exists. Orlistat was approved for use in Europe in July
1998, and the FDA granted approval for use in adults in April 1999. In December
2003 the FDA approved orlistat for use in obese adolescents 12 to 16 years of
age.
Glaxo SmithKline, the manufacturer of Xenical®, filed a switch to
over-the-counter (OTC) application in June 2005 for a reduced dose product. An
FDA Joint Advisory Committee recommended approval in January 2006. On February
7, 2007, the FDA approved Alli™, an orlistat 60 mg capsules for OTC use.
Mechanism of Action:
Orlistat produces weight
loss through inhibition of nutrient absorption.
A covalent bond is formed with
the active serine residue site of gastric and pancreatic lipases within the
lumen of the stomach and the small intestine. As these enzymes become
unavailable to hydrolyze dietary triglycerides into free fatty acids and
monoglycerides, less fat is absorbed by the body.
This results in decreased
caloric intake that may result in negative energy balance and weight loss.
Therefore, systemic absorption of the drug is not needed to produce a
weight-lowering effect. At the recommended therapeutic dose of 120 mg orlistat
PO three times per day, dietary fat absorption is inhibited by approximately
30%.
Pharmacokinetics:
Orlistat is administered orally and has minimal systemic absorption. Sporadic
intact amounts of orlistat, low plasma concentration levels (<10 ng/ml), and
no evidence of accumulation were observed during therapeutic studies. In vitro, orlistat was > 99%
bound to plasma proteins (primarily lipoproteins and albumin) with minimal
partitioning into erythrocytes.
Metabolism of orlistat to weakly active and
inactive metabolites is believed to occur mainly within the gastrointestinal
wall. Approximately 83% of a single oral dose of orlistat was excreted
unchanged in the feces. Renal excretion was < 2% of the dose. Complete
excretion of both urinary and fecal orlistat was reached in 3 to 5 days. The
estimated half-life of the absorbed portion of orlistat was approximately 1 to
2 hours.
•Route-Specific Pharmacokinetics
Oral Route
Peak plasma concentrations of orlistat (<5 ng/ml) occurred approximately 8
hours after a 360 mg dose. Based on fecal fat measurements, the effect of
orlistat may be seen within 24 to 48 hours.
