A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Xenical Pharmacology, Pharmacokinetics, Studies, Metabolism - Orlistat
Xenical Pharmacology, Pharmacokinetics, Studies, Metabolism - Orlistat
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
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
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,
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, or warfarin. XENICAL induced a modest
increase of the bioavailability
and lipid-lowering effect
of pravastatin (see CLINICAL STUDIES and PRECAUTIONS).
Alcohol did not affect
the pharmacodynamics
of orlistat.
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 (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 (e.g., type
2 diabetes, lipids,
blood pressure) were assessed
in seven long-term (1- to 2-years duration) multicenter, double-blind,
placebo-controlled clinical trials. During the first year of therapy,
weight loss
and weight maintenance were assessed. 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 these 7 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 ³5%
and ³10% 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
³5% and ³10%
of Body Weight From Randomization After 1-Year Treatment*
|
Intent-to-Treat Population#
|
|
³5%
Weight Loss
|
³10%
Weight Loss
|
| Study No. |
XENICAL
n |
Placebo
n |
p-value
|
XENICAL
n |
Placebo
n |
p-value |
| 14119B |
35.5%
110 |
21.3%
108 |
0.021
|
16.4%
110 |
6.5%
108 |
0.022 |
| 14119C |
54.8%
343 |
27.4%
340 |
< 0.001
|
24.8%
343 |
8.2%
340 |
<
0.001 |
| 14149 |
50.6%
241 |
26.3%
236 |
< 0.001
|
22.8%
241 |
11.9%
236 |
0.02 |
| 14161## |
37.1%
210 |
16.0%
212 |
< 0.001
|
19.5%
210 |
3.8%
212 |
<
0.001 |
| 14185 |
42.6%
657 |
22.4%
223 |
< 0.001
|
17.7%
657 |
9.9%
223 |
0.006 |
The diet
utilized during year 1 was a reduced-calorie diet.
* Treatment designates XENICAL 120 mg
three times a day plus diet
or placebo plus diet
# Last observation carried forward
## 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
| Risk
Factor |
XENICAL 120 mg#
|
Placebo#
|
| Metabolic: |
| Total
Cholesterol |
-2.0%
|
+5.0% |
| LDL-Cholesterol |
-4.0%
|
+5.0% |
| HDL-Cholesterol |
+9.3%
|
+12.8%
|
| LDL/HDL |
-0.37
|
-0.20
|
| Triglycerides |
+1.34%
|
+2.9%
|
| Fasting
Glucose, mmol/L |
-0.04
|
+0.0
|
| Fasting
Insulin, pmol/L |
-6.7
|
+5.2
|
| Cardiovascular: |
| Systolic
Blood Pressure, mm Hg |
-1.01
|
+0.58
|
| Diastolic
Blood Pressure, mm Hg |
-1.19
|
+0.46
|
| Anthropometric: |
| Waist
Circumference, cm |
-6.45
|
-4.04
|
| Hip Circumference,
cm |
-5.31
|
-2.96
|
* Treatment designates XENICAL 120 mg
three times a day plus diet
or placebo plus diet
# Intent-to-treat population
at week 52, observed data based on pooled data from 5 studies
Population With Abnormal Risk Factors at Randomization:
The changes from randomization
following 1-year treatment
in the population
with abnormal lipid
levels (LDL ³ 130 mg/dL, LDL/HDL ³
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 ³140 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 ³
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 (³120 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 (³100
cm).
Effect on Weight Regain: Three studies were designed
to evaluate 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 evaluate 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 ³ 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 ³5%
and ³10% weight
loss after 2 years are
shown in Table 3.
Table 3. Percentage of Patients Losing
³5% and ³10%
of Body Weight From Randomization After 2-Year Treatment*
|
Intent-to-Treat Population#
|
|
³5%
Weight Loss
|
³10%
Weight Loss
|
| Study No. |
XENICAL
n |
Placebo
n |
p-value
|
XENICAL
n |
Placebo
n |
p-value
|
| 14119C |
45.1%
133 |
23.6%
123 |
< 0.001
|
24.8%
133 |
6.5%
123 |
< 0.001
|
| 14149 |
43.3%
178 |
27.2%
158 |
0.002
|
18.0%
178 |
9.5%
158 |
0.025
|
| 14161## |
25.0%
148 |
15.0%
113 |
0.049
|
16.9%
148 |
3.5%
113 |
0.001
|
| 14185 |
34.0%
147 |
27.9%
122 |
0.279
|
17.7%
147 |
11.5%
122 |
0.154
|
The diet
utilized during year 2 was designed for weight maintenance and not
weight loss.
* Treatment designates XENICAL 120 mg
three times a day plus diet
or placebo plus diet
# Last observation carried forward
## 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.
Study of Patients With Type 2 Diabetes: A 1-year
double-blind, placebo-controlled study in type 2 diabetics (N=321)
stabilized on sulfonylureas was conducted. Thirty percent of patients
treated with XENICAL achieved at least a 5% or greater reduction
in body weight
from randomization
compared to 13% of the placebo-treated patients (p<0.001). Table
4 describes the changes over 1 year of treatment with XENICAL compared
to placebo, in sulfonylurea
usage and dose reduction
as well as in hemoglobin
HbA1c, fasting glucose,
and insulin.
Table 4. Mean Changes in Body Weight and Glycemic
Control From Randomization Following 1-Year Treatment in Patients
With Type 2 Diabetes
|
XENICAL
120 mg*
(n=162) |
Placebo*
(n=159)
|
Statistical Significance
|
| % patients who discontinued
dose of oral
sulfonylurea
% patients who decreased dose
of oral sulfonylurea
|
11.7%
31.5%
|
7.5%
21.4%
|
#
|
| Average reduction
in sulfonylurea
medication dose |
-22.8% |
-9.1% |
#
|
| Body weight
change (lbs) |
-8.9 |
-4.2 |
#
|
| HbA1c |
-0.18% |
+0.28% |
#
|
| Fasting glucose,
mmol/L |
-0.02 |
+0.54 |
#
|
| Fasting insulin,
pmol/L |
-19.68 |
-18.02 |
ns
|
Statistical significance based on intent-to-treat
population, last observation carried forward.
* Treatment designates XENICAL 120 mg
three times a day plus diet
or placebo plus diet.
# Statistically significant
(p£ 0.05) based on intent-to-treat,
last observation carried forward.
ns nonsignificant, p>0.05
In addition, XENICAL (n=162) compared to placebo
(n=159) was associated with significant
lowering for total cholesterol
(-1.0% vs +9.0%, p£ 0.05), LDL-cholesterol
(-3.0% vs +10.0%, p£ 0.05), LDL/HDL
ratio (-0.26 vs -0.02,
p£ 0.05) and triglycerides
(+2.54% vs +16.2%, p£0.05), respectively.
For HDL cholesterol,
there was a +6.49% increase on XENICAL and +8.6% increase on placebo,
p> 0.05. Systolic blood
pressure increased
by +0.61 mm Hg on XENICAL and increased by +4.33 mm Hg
on placebo, p> 0.05.
Diastolic blood pressure
decreased by -0.47 mm Hg for XENICAL and by -0.5 mm Hg
for placebo, p> 0.05.
Glucose Tolerance in Obese Patients: Two-year studies
that included oral glucose
tolerance tests were conducted in obese
patients not previously diagnosed or treated for type
2 diabetes and whose
baseline oral
glucose tolerance
test (OGTT) status at randomization
was either normal, impaired,
or diabetic.
The progression
from a normal OGTT at randomization
to a diabetic or impaired
O.T. following 2 years
of treatment with
XENICAL (n=251) or placebo
(n=207) were compared. Following treatment with XENICAL, 0.0% and
7.2% of the patients progressed from normal to diabetic
and normal to impaired,
respectively, compared to 1.9% and 12.6% of the placebo
treatment group, respectively.
In patients found to have an impaired O.T.
at randomization, the percent
of patients improving to normal or deteriorating to diabetic
status following 1 and
2 years of treatment with XENICAL compared to placebo
are presented. After 1 year of treatment, 45.8% of the placebo
patients and 73% of the XENICAL patients had a normal oral glucose
tolerance test
while 10.4% of the placebo
patients and 2.6% of the XENICAL patients became diabetic. After
2 years of treatment,
50% of the placebo patients
and 71.7% of the XENICAL patients had a normal oral glucose
tolerance test
while 7.5% of placebo
patients were found to be diabetic
and 1.7% of XENICAL patients were found to be diabetic
after treatment.
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