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Precose Pharmacology, Pharmacokinetics, Studies, Metabolism - Acarbose
Precose Pharmacology, Pharmacokinetics, Studies, Metabolism - Acarbose
PHARMACOLOGY
Acarbose is a complex oligosaccharide
that delays the digestion
of ingested carbohydrates, thereby resulting in a smaller rise in blood
glucose concentration following
meals. As a consequence
of plasma glucose
reduction, PRECOSE ® reduces levels of glycosylated hemoglobin
in patients with type 2 diabetes
mellitus. Systemic non-enzymatic protein
glycosylation, as reflected by levels of glycosylated hemoglobin,
is a function of average
blood glucose concentration
over time.
Mechanism of Action
In contrast to sulfonylureas,
PRECOSE ® does not enhance insulin
secretion. The antihyperglycemic action
of acarbose results from
a competitive, reversible
inhibition of pancreatic
alpha-amylase complex starches to oligosaccharides in the lumen
of the small intestine, while the membrane-bound intestinal
and membrane-bound intestinal
alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes
complex starches to oligosaccharides
in the lumen of the small intestine,
while the membrane-bound intestinal
alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides
to glucose and other monosaccharides in the brush border
of the small intestine. In diabetic patients, this enzyme
inhibition results in a
delayed glucose absorption and a lowering of postprandial
hyperglycemia.
Because its mechanism of
action is different, the effect
of PRECOSE ® to that of sulfonylureas, insulin
or metformin when used in
combination. In addition, PRECOSE® diminishes the insulinotropic and
weight-increasing effects of sulfonylureas. Acarbose has no
inhibitory activity
against lactase and consequently would not be expected to induce lactose
intolerance.
Pharmacokinetics
Absorption: In a study of 6 healthy
men, less than 2% of an oral
dose of acarbose
was absorbed as active drug,
while approximately 35% of total radioactivity
from a 14C-labeled oral
dose was absorbed. An
average of 51% of an oral
dose was excreted in the feces
as unabsorbed drug-related radioactivity
within 96 hours of ingestion.
Because acarbose acts locally
within the gastrointestinal
tract, this low systemic
bioavailability of
parent compound
is therapeutically desired. Following oral
dosing of healthy volunteers
with 14C-labeled acarbose peak plasma
concentrations of radioactivity
were attained 14-24 hours after dosing, while peak plasma
acarbose, concentrations of active drug were attained at approximately
1 hour. The delayed absorption
of acarbose-related radioactivity reflects the absorption
of metabolites that may be formed by either intestinal
bacteria or intestinal
enzymatic hydrolysis.
Metabolism: Acarbose is metabolized exclusively within
the gastrointestinal
tract, principally by intestinal
bacteria. A fraction of these
metabolites (approximately 34% of the dose) was absorbed and subsequently
excreted in the urine. At least
13 metabolites have been separated chromato-graphically from urine
specimens. The major metabolites have been identified as 4-methylpyrogallol
derivatives (i. e., sulfate, methyl, and glucuronide
conjugates). One metabolite
(formed by cleavage of a
glucose molecule
from acarbose) also has alpha-glucosidase inhibitory activity. but also
by digestive enzymes. A
fraction of these metabolites
(approximately 34% of the dose) was from urine
specimens. This metabolite, together with the parent
compound, recovered from
the urine, accounts for less than 2% of the total administered dose. .
Excretion: The fraction
of acarbose that is absorbed
as intact drug is almost completely
excreted by the kidneys. When acarbose was given intravenously, 89% of
the dose was recovered in the
urine as active drug
within 48 hours. In contrast, less
than 2% of an oral dose was recovered
in the urine as active (i. e.,
parent compound
and active metabolite) drug. This is consistent with the low bioavailability
of the parent drug. The plasma
elimination half-life
of acarbose activity
is approximately 2 hours in healthy
volunteers. Consequently, drug
accumulation does not occur with three times a day (t. i. d.) oral
dosing.
Special Populations
The mean steady-state area
under the curve (AUC) and maximum
concentrations of acarbose
were approximately 1.5 times higher in elderly compared to young volunteers;
however, these differences were not statistically significant. Patients
with severe renal impairment
(Clcr< 25 mL/min/1.73m2) attained about 5 times
higher peak plasma concentrations
of acarbose and 6 times larger
A.C. than volunteers with normal
renal function. No
studies of acarbose pharmacokinetic
parameters according to race
have been performed. In U. S. controlled clinical
studies of PRECOSE ® in patients with type
2 diabetes mellitus, reductions
in glycosylated hemoglobin levels were similar in Caucasians (n= 478)
and African-Americans (n= 167), with a trend
toward a better response
in Latinos (n= 132).
Drug-Drug Interactions
Studies in healthy volunteers
have shown that PRECOSE ® has no
effect on either the pharmacokinetics
or pharmacodynamics of digoxin, nifedipine, propranolol, or ranitidine. PRECOSE ® did
not interfere with the absorption or disposition of the sulfonylurea glyburide
in diabetic patients. PRECOSE ® may affect digoxin bioavailabillty and may require dose adjustment
of digoxin by 16% (90% confidence interval: 8-23%), decrease mean C max digoxin by 26%
(90% confidence interval: 16-34%) and decrease mean trough concentrations of digoxin by 9% (90% confidence limit:
19% decrease to 2% increase). (See PRECAUTIONS Drug Interactions).
The amount of metformin absorbed while taking PRECOSE® was bioequivalent to the amount absorbed
when taking placebo, as indicated
by the plasma AUC values. However, the peak plasma
level of metformin was reduced
by approximately 20% when taking PRECOSE ® due to a slight delay in
the absorption of metformin. There is little if any clinically significant
interaction between PRECOSE ® and metformin.
Clinical Trials
Clinical Experience from Dose Finding Studies in Type 2 Diabetes
Mellitus Patients on Dietary Treatment Only: Results from six
controlled, fixed-dose, monotherapy
studies of PRECOSE ® diabetes
mellitus, involving 769 PRECOSE ®-treated patients, were combined
and a weighted average of the difference from placebo
in the mean change from baseline
in glycosylated hemoglobin (HbA1c) was calculated for each dose
level as presented below:
Table 1.
|
Mean Placebo-Subtracted Change in HbA1c in Fixed-Dose Monotherapy
Studies
|
|
Dose of PRECOSE*
|
N
|
Change in HbA1c %
|
p-Value
|
| 25 mg
t. i. d. |
110
|
-0.44
|
0.0307
|
| 50 mg
t. i. d. |
131
|
-0.77
|
0.0001
|
| 100 mg
t. i. d. |
244
|
-0.74
|
0.0001
|
| 200 mg
t. i. d.** |
231
|
-0.86
|
0.0001
|
| 300 mg
t.i.d.** |
53
|
-1.00
|
0.0001
|
* PRECOSE ® was statistically significantly different
from placebo at all doses.
Although there were no statistically
significant differences among the mean
results for doses ranging from 50 to 300 mg t.i.d., some patients may
derive benefit by increasing
the dosage from 50 to 100 mg
t.i.d.
** Although studies utilized a maximum
dose of 200 or 300 mg
t.i.d., the maximum recommended
dose for patients < 60 kg
is 50 mg t. i. d.; the maximum
recommended dose for patients
> 60 kg is 100 mg
t. i. d.
Results from these six fixed-dose, monotherapy
studies were also combined to derive a weighted average
of the difference from placebo
in mean change from baseline
for one-hour postprandial
plasma glucose
levels as shown in the following table:
Table 2.
|
Dose of PRECOSE ® (t.i.d.)*
|
N
|
Mean Change in plasma
glucose (mg/dL)
|
|
25 mg
|
110
|
-25
|
|
50 mg
|
131
|
-35
|
|
100 mg
|
244
|
-46
|
|
200 mg
|
231
|
-50
|
|
300 mg
|
53
|
-83
|
* PRECOSE ® was statistically significantly different
from placebo at all doses
with respect to effect on one-hour
postprandial plasma glucose.
** The 300 mg t.
i. d. PRECOSE ® regimen
was superior to lower doses, but there were no
statistically significant
differences from 50 to 200 mg t.
i. d.
Clinical Experience in Type 2 Diabetes Mellitus Patients on Monotherapy,
or in Combination with Sulfonylureas, Metformin or Insulin: PRECOSE
® was studied as monotherapy
and as combination therapy
to sulfonylurea, metformin, or insulin
treatment. The treatment
effects on HbA1c levels and one-hour postprandial
glucose levels are summarized
for four placebo-controlled, double-blind, randomized studies conducted
in the United States in Tables 3 and 4, respectively. The placebo-subtracted
treatment differences, which
are summarized below, were statistically significant
for both variables in all of these studies.
Study 1 (n= 109) involved patients on background treatment
with diet only. The mean effect
of the addition of PRECOSE
® to diet therapy was a change
in HbA1c of -0.78%, and an improvement of one-hour postprandial glucose
of -74.4 mg/dL.
In Study 2 (n= 137), the mean
effect of the addition
of PRECOSE ® to maximum
sulfonylurea therapy
was a change in HbA1c of -0.54%, and an improvement of one-hour postprandial
glucose of -33.5 mg/dL.
In Study 3 (n= 147), the mean
effect of the addition
of PRECOSE ® to maximum
metformin therapy
was a change in HbA1c of -0.65%, and an improvement of one-hour postprandial
glucose of -34.3 mg/dL.
Study 4 (n= 145) demonstrated that PRECOSE ® added to patients on
background treatment with
insulin resulted in a mean
change in HbA1c of -0.69%, and an improvement of one-hour postprandial
glucose of -36.0 mg/dL.
A one year study of PRECOSE ® as monotherapy
or in combination with sulfonylurea, metformin
or insulin treatment
was conducted in Canada in which 316 patients were included in the primary
efficacy analysis
(Figure 2). In the diet,
sulfonylurea and metformin
groups, the mean decrease in
HbA1c produced by the addition
of PRECOSE ® was statistically significant at six months, and this
effect was persistent at one
year. In the PRECOSE ® -treated
patients on insulin, there
was a statistically significant reduction in HbA1c at six months, and
a trend for a reduction
at one year.
Table 3. Effect of Precose ® on HbA1c.
|
Study
|
Treatment
|
HbA1c (%) a
|
p-Value
|
|
Mean Baseline
|
Mean change from baseline
b
|
Treatment Difference
|
|
1
|
Placebo Plus Diet |
8.67
|
+0.33
|
—
|
—
|
| PRECOSE 100 mg
t. i. d. Plus Diet |
8.69
|
-0.45
|
-0.78
|
0.0001
|
|
2
|
Placebo Plus SFU c |
9.56
|
+0.24
|
—
|
—
|
| PRECOSE 50-300 d
mg t. i. d. Plus SFU c |
9.64
|
-0.30
|
-0.54
|
0.0096
|
|
3
|
Placebo Plus Metformin
e |
8.17
|
+0.08 g
|
——
|
|
| PRECOSE 50-100 mg
t. i. d. Plus Metformin e |
8.46
|
-0.57 g
|
-0.65
|
0.0001
|
|
4
|
Placebo Plus Insulin f |
8.69
|
+0.11
|
—
|
—
|
| PRECOSE 50-100 mg
t. i. d. Plus Insulinf |
8.77
|
-0.58
|
-0.69
|
0.0001
|
a HbA1c Normal Range: 4 -6%
b After four months treatment in Study 1, and six months in Studies 2, 3, and 4
c SFU, sulfonylurea, maximum dose
d Although studies utilized a maximum
dose of up to 300 mg
t. i. d., the maximum recommended
dose for ≤ 60 kg
is 50 mg t. i. d.; the maximum
recommended dose for patients
> 60 kg is 100 mg
t. i. d.
e Metformin dosed at 2000 mg/day or 2500 mg/day
f Mean dose of insulin 61 U/day
g Results are adjusted to a common baseline
of 8.33%
Table 4. Effect of Precose ® on Postprandial Glucose
|
One-Hour Postprandial Glucose (mg/dL)
|
|
Study
|
Treatment
|
Mean Baseline
|
Mean change from baseline
a
|
Treatment Difference
|
p-Value
|
|
1
|
Placebo Plus Diet |
297.1
|
+31.8
|
—
|
—
|
| PRECOSE 100 mg
t. i. d. Plus Diet |
299.1
|
-42.6
|
-74.4
|
0.0001
|
|
2
|
Placebo Plus SFU b |
308.6
|
+6.2
|
—
|
—
|
| PRECOSE 50-300 c
mg t. i. d. Plus SFU b |
311.1
|
-27.3
|
-33.5
|
0.0017
|
|
3
|
Placebo Plus Metformin
d |
263.9
|
+3.3 f
|
—
|
—
|
| PRECOSE 50-100 mg
t. i. d. Plus Metformin d |
283.0
|
-31.0 f
|
-34.3
|
0.0001
|
|
4
|
Placebo Plus Insulin e |
279.2
|
+8.0
|
—
|
—
|
| PRECOSE 50-100 mg
t. i. d. Plus Insulin e |
277.8
|
-28.0
|
-36.0
|
0.0178
|
a After four months treatment
in Study 1, and six months in Studies 2, 3, and 4
b SFU, sulfonylurea, maximum
dose
c Although studies utilized a maximum
dose of up to 300 mg
t.i.d., the maximum recommended
dose for patients ≤ 60 kg
is 50 mg t. i. d.; the maximum
recommended dose for patients
> 60 kg is 100 mg
t. i. d.
d Metformin dosed at 2000 mg/day or 2500 mg/day
e Mean dose of insulin
61 U/day
f Results are adjusted to a common baseline
of 273 mg/dL
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