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
Glucovance Pharmacology, Pharmacokinetics, Studies, Metabolism - Glyburide and Metformin
Glucovance Pharmacology, Pharmacokinetics, Studies, Metabolism - Glyburide and Metformin
CLINICAL PHARMACOLOGY
Mechanism of Action
GLUCOVANCE combines metformin
hydrochloride and glyburide,
two antihyperglycemic agents with complementary mechanisms of action,
to improve glycemic control in patients with type
2 diabetes.
Glyburide appears to lower blood
glucose acutely by stimulating
the release of insulin from
the pancreas, an effect dependent
upon functioning beta cells in
the pancreatic islets.
The mechanism by which glyburide
lowers blood glucose during
long-term administration
has not been clearly established. With chronic administration
in patients with type 2 diabetes,
the blood glucose
lowering effects persists despite a gradual decline
in the insulin secretory
response to the drug. Extra-pancreatic effects may be involved in the
mechanism of action of oral
sulfonylulrea hypoglycemic drugs.
Metformin hydrochloride
is an antihyperglycemic agent
that improves glucose tolerance
in patients with type 2 diabetes,
lowering both basal and postprandial
plasma glucose. Metformin hydrochloride
decreases hepatic glucose
production, decreases intestinal
absorption of glucose,
and improves insulin sensitivity
by increasing peripheral
glucose uptake
and utilization.
Pharmacokinetics
Absorption and Bioavailability
GLUCOVANCE
In bioavailability
studies of GLUCOVANCE 2.5 mg/500 mg
and 5 mg/500 mg, the mean area
under the plasma concentration
time curve
(AUC) for the glyburide component
was 18% and 7%, respectively, greater than that of the Micronase® brand
of glyburide coadministered
with metformin. The glyburide
component of GLUCOVANCE,
therefore, is not bioequivalent to Micronase®. The metformin component
of GLUCOVANCE is bioequivalent
to metformin coadministered
with glyburide.
Following administration
of a single GLUCOVANCE 5 mg/500 mg
tablet, with either a 20% glucose
solution or a 20% glucose
solution with food, there
was no effect of food on the
C max and a relatively small effect
of food on the AUC
of the glyburide component.
The T max for the glyburide
component was shortened from 7.5 hours to 2.75 hours with food
compared to the same tablet strength
administered fasting with
a 20% glucose solution. The
clinical significance of
an earlier T max for glyburide
after food is not known. The
effect of food on the pharmacokinetics
of the metformin component
was indeterminate.
Glyburide
Single-dose studies with Micronase® tablets in normal
subjects demonstrate significant
absorption of glyburide
within one hour, peak drug levels
at about four hours, and low but detectable levels at twenty-four hours.
Mean serum levels of glyburide,
as reflected by areas under the serum
concentration-time curve, increase in proportion to corresponding
increases in dose. Bioequivalence has not been established between GLUCOVANCE
(Glyburide and Metformin HCl tablets) and single ingredient
glyburide products.
Metformin hydrochloride
The absolute bioavailability
of a 500 mg metformin
hydrochloride tablet
given under fasting conditions
is approximately 50-60%. Studies using single oral doses of metformin
tablets of 500 mg and 1500 mg,
and 850 mg to 2550 mg, indicate
that there is a lack of dose
proportionality with increasing doses, which is due to decreased absorption
rather than an alteration in elimination. Food decreases the extent of
and slightly delays the absorption
of metformin, as shown by approximately a 40% lower peak concentration
and a 25% lower AUC in plasma
and a 35 minute prolongation of time
to peak plasma concentration
following administration
of a single 850 mg tablet
of metformin with food,
compared to the same tablet
strength administered fasting. The clinical
relevance of these decreases is unknown.
Distribution
Glyburide
Sulfonylurea drugs are extensively bound
to serum proteins. Displacement
from protein binding sites
by other drugs may lead to enhanced
hypoglycemic action. In vitro , the protein
binding exhibited by glyburide
is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide,
tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas
from serum proteins to a far
greater extent than the non-ionic binding glyburide. It has not been shown
that this difference in protein
binding results in fewer drug-drug interactions with glyburide
tablets in clinical use.
Metformin hydrochloride
The apparent volume
of distribution (V/F)
of metformin following single
oral doses of 850 mg averaged 654±358
L. Metformin is negligibly bound
to plasma proteins. Metformin partitions into erythrocytes, most likely
as a function of time. At usual
clinical doses and dosing
schedules of metformin, steady state plasma
concentrations of metformin
are reached within 24-48 hours and are generally <1 µg/mL. During controlled
clinical trials, maximum
metformin plasma
levels did not exceed 5 µg/mL, even at maximum
doses.
Metabolism and Elimination
Glyburide
The decrease of glyburide
in the serum of normal
healthy individuals is biphasic;
the terminal half-life
is about 10 hours. The major metabolite
of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the
3-cis-hydroxy derivative, also occurs. These metabolites probably contribute
no significant hypoglycemic
action in humans since they
are only weakly active (1/400 th and 1/40 th as
active, respectively, as glyburide) in rabbits. Glyburide is excreted
as metabolites in the bile and
urine, approximately 50% by each route. This dual excretory
pathway is qualitatively different
from that of other sulfonylureas, which are excreted primarily in the
urine.
Metformin hydrochloride
Intravenous single-dose studies in normal
subjects demonstrate that metformin is excreted unchanged in the urine
and does not undergo hepatic
metabolism (no metabolites
have been identified in humans) nor biliary
excretion. Renal clearance (see Table 1 ) is approximately 3.5
times greater than creatinine
clearance, which indicates that tubular
secretion is the major route
of metformin elimination.
Following oral administration,
approximately 90% of the absorbed drug
is eliminated via the renal
route within the first 24 hours, with a plasma
elimination half-life
of approximately 6.2 hours. In
blood, the elimination
half-life is approximately
17.6 hours, suggesting that the erythrocyte
mass may be a compartment of
distribution.
Special Populations
Patients With Type 2 Diabetes
Multiple-dose studies with glyburide
in patients with type 2 diabetes
demonstrate drug level concentration-time
curves similar to single-dose studies, indicating no buildup of drug
in tissue depots.
In the presence of normal
renal function, there are no
differences between single- or multiple-dose pharmacokinetics
of metformin between patients
with type 2 diabetes
and normal subjects (see Table
1 ), nor is there any accumulation of metformin
in either group at usual clinical
doses.
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients with hepatic
insufficiency for either glyburide
or metformin.
Renal Insufficiency
No information is available on the pharmacokinetics
of glyburide in patients
with renal insufficiency.
In patients with decreased renal
function (based on creatinine
clearance), the plasma and
blood half-life
of metformin is prolonged
and the renal clearance is decreased
in proportion to the decrease in creatinine
clearance (see Table
1 ; also, see WARNINGS).
Geriatrics
There is no information on the pharmacokinetics
of glyburide in elderly
patients. Limited data from controlled pharmacokinetic studies of metformin
in healthy elderly subjects suggest that total plasma
clearance is decreased,
the half-life is prolonged, and C max is increased, compared
to healthy young subjects.
From these data, it appears that the change in metformin
pharmacokinetics
with aging is primarily accounted
for by a change in renal function
(see Table 1 ). Metformin treatment
should not be initiated in patients ≥80 years of age
unless measurement of creatinine
clearance demonstrates that
renal function is not reduced.
Table 1. Select Mean (±S.D.) Metformin Pharmacokinetic
Parameters
Following Single or Multiple Oral Doses of Metformin
|
Subject Groups: Metformin
dose a (number
of subjects)
|
C max b
(µg/mL) |
T max c
(hrs) |
Renal
Clearance
(mL/min) |
|
Healthy, nondiabetic adults:
|
|
500 mg
SD d (24)
|
1.03 (±0.33) |
2.75 (±0.81) |
600 (±132) |
|
850 mg
SD (74) e
|
1.60 (±0.38) |
2.64 (±0.82) |
552 (±139) |
|
850 mg
t.i.d. for 19 doses f (9)
|
2.01 (±0.42) |
1.79 (±0.94) |
642 (±173) |
|
Adults with type
2 diabetes:
|
|
850 mg
SD (23)
|
1.48 (±0.5) |
3.32 (±1.08) |
491 (±138) |
|
850 mg
t.i.d. for 19 doses f (9)
|
1.90 (±0.62) |
2.01 (±1.22) |
550 (±160) |
|
Elderly g , healthy
nondiabetic adults:
|
|
850 mg
SD (12)
|
2.45 (±0.70) |
2.71 (±1.05) |
412 (±98) |
|
Renal-impaired adults: 850 mg
SD
|
|
|
Mild (CL cr h 61-90
mL/min) (5)
|
1.86 (±0.52) |
3.20 (±0.45) |
384 (±122) |
|
Moderate (CL cr 31-60 mL/min) (4)
|
4.12 (±1.83) |
3.75 (±0.50) |
108 (±57) |
|
Severe (CL cr 10-30 mL/min) (6)
|
3.93 (±0.92) |
4.01 (±1.10) |
130 (±90) |
|
a -All doses given fasting
except the first 18 doses of the multiple-dose studies
|
|
b -Peak plasma
concentration
|
|
c -Time to peak plasma
concentration
|
|
d -SD = single dose
|
|
e -Combined results (average means) of
five studies: mean age
32 years (range 23-59 years)
|
|
f -Kinetic study done following dose
19, given fasting
|
|
g -Elderly subjects, mean
age 71 years (range 65-81
years)
|
|
h -CL cr = creatinine
clearance normalized to body
surface area
of 1.73 m 2
|
Pediatrics
No data from pharmacokinetic studies in pediatric
subjects are available for either glyburide
or metformin.
Gender
There is no information on the effect
of gender on the pharmacokinetics
of glyburide. Metformin pharmacokinetic parameters did not differ significantly
in subjects with or without type
2 diabetes when analyzed
according to gender (males = 19, females = 16). Similarly, in controlled
clinical studies in patients
with type 2 diabetes, the antihyperglycemic
effect of metformin
was comparable in males and females.
Race
No information is available on race
differences in the pharmacokinetics
of glyburide. No studies of metformin
pharmacokinetic parameters according to race have been performed. In
controlled clinical studies
of metformin in patients
with type 2 diabetes, the antihyperglycemic
effect was comparable in whites
(n=249), blacks (n=51), and Hispanics (n=24).
Clinical Studies
Initial Therapy
In a 20-week, double-blind, multicenter U.S. clinical
trial, a total of 806 drug-naive patients with type
2 diabetes, whose hyperglycemia
was not adequately controlled with diet
and exercise alone (baseline
fasting plasma
glucose [FPG] < 240 mg/dL,
baseline hemoglobin
A1c [HbA 1c ] between 7% and 11%), were randomized to receive
initial therapy
with placebo, 2.5 mg glyburide,
500 mg metformin, GLUCOVANCE 1.25
mg/250 mg, or GLUCOVANCE (Glyburide and Metformin HCl Tablets) 2.5 mg/500
mg. After four weeks, the dose
was progressively increased (up to the eight-week visit) to a maximum
of four tablets daily as needed to reach a target
FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2
.
Table 2. Placebo- and Active-Controlled Trial
of GLUCOVANCE as Initial Therapy: Summary
of Trial Data at 20 Weeks
|
|
Placebo |
Glyburide
2.5 mg tablets |
Metformin
500 mg tablets |
GLUCOVANCE
1.25 mg/250 mg tablets |
GLUCOVANCE
2.5 mg/500 mg tablets |
|
Mean Final Dose
|
0 mg |
5.3 mg |
1317 mg |
2.78 mg/557 mg
|
4.1 mg/824 mg
|
|
Hemoglobin A 1c
|
N=147 |
N=142 |
N=141 |
N=149 |
N=152 |
|
Baseline Mean (%)
|
8.14 |
8.14 |
8.23 |
8.22 |
8.20 |
|
Mean Change from Baseline
|
-0.21 |
-1.24 |
-1.03 |
-1.48 |
-1.53 |
|
Difference from Placebo
|
|
-1.02 |
-0.82 |
-1.26 a |
-1.31 a |
|
Difference from Glyburide
|
|
|
|
-0.24 b |
-0.29 b |
|
Difference from Metformin
|
|
|
|
-0.44 b |
-0.49 b |
|
Fasting Plasma Glucose
|
N=159 |
N=158 |
N=156 |
N=153 |
N=154 |
|
Baseline Mean FPG (mg/dL)
|
177.2 |
178.9 |
175.1 |
178 |
176.6 |
|
Mean Change from Baseline
|
4.6 |
-35.7 |
-21.2 |
-41.5 |
-40.1 |
|
Difference from Placebo
|
|
-40.3 |
-25.8 |
-46.1 a |
-44.7 a |
|
Difference from Glyburide
|
|
|
|
-5.8 c |
-4.5 c |
|
Difference from Metformin
|
|
|
|
-20.3 c |
-18.9 c |
|
Body Weight Mean Change from Baseline
|
-0.7 kg |
+ 1.7 kg |
-0.6 kg |
+ 1.4 kg |
+ 1.9 kg |
|
Final HbA 1c Distribution (%)
|
N=147 |
N=142 |
N=141 |
N=149 |
N=152 |
|
< 7%
|
19.7% |
59.9% |
50.4% |
66.4% |
71.7% |
|
≥7% and < 8%
|
37.4% |
26.1% |
29.8% |
25.5% |
19.1% |
|
≥8%
|
42.9% |
14.1% |
19.9% |
8.1% |
9.2% |
|
a p < 0.001 b p
< 0.05 c p = NS
|
Treatment with GLUCOVANCE (Glyburide and Metformin HCl Tablets) resulted
in significantly greater reduction
in HbA 1c and postprandial
plasma glucose (PPG) compared
to glyburide, metformin, or placebo. Also, GLUCOVANCE therapy
resulted in greater reduction
in FPG compared to glyburide, metformin, or placebo, but the differences
from glyburide and metformin
did not reach statistical significance.
Changes in the lipid profile
associated with GLUCOVANCE treatment
were similar to those seen with glyburide, metformin, and placebo.
The double-blind placebo-controlled trial described above restricted
enrollment to patients with HbA 1c <11% or FPG < 240
mg/dL. Screened patients ineligible for the first trial because of HbA
1c and/or FPG exceeding these limits were treated directly
with GLUCOVANCE 2.5 mg/500 mg in
an open-label uncontrolled protocol. In
this study, three out of 173 patients (1.7%) discontinued because of inadequate
therapeutic response.
Across the group of 144 patients
who completed 26 weeks of treatment, mean
HbA 1c was reduced from a baseline
of 10.6% to 7.1%. The mean baseline
FPG was 283 mg/dL and was reduced to 164 and 161 mg/dL after 2 and 26
weeks, respectively. The mean
final titrated dose of GLUCOVANCE
was 7.85 mg/1569 mg (equivalent
to approximately three GLUCOVANCE 2.5 mg/500 mg
tablets per day).
Second Line Therapy
In a 16-week, double-blind, active-controlled U.S. clinical
trial, a total of 639 patients with type
2 diabetes not adequately
controlled (mean baseline HbA 1c 9.5%, mean
baseline FPG 213 mg/dL) while
being treated with at least one-half the maximum
dose of a sulfonylurea
(e.g., glyburide 10 mg,
glipizide 20 mg) were randomized
to receive glyburide (fixed
dose, 20 mg), metformin (500 mg), GLUCOVANCE 2.5 mg/500 mg, or GLUCOVANCE
5 mg/500 mg. The doses of metformin
and GLUCOVANCE were titrated to a maximum
of four tablets daily as needed to achieve FPG < 140 mg/dL. Trial data
at 16 weeks are summarized in Table 3 .
Table 3. GLUCOVANCE as Second-Line Therapy:
Summary of Trial Data at 16 Weeks
|
|
Glyburide
5 mg
tablets |
Metformin
500 mg
tablets |
GLUCOVANCE
2.5 mg/500 mg
tablets |
GLUCOVANCE
5 mg/500 mg
tablets |
|
Mean Final Dose
|
20 mg |
1840 mg |
8.8 mg/1760 mg
|
17 mg/1740 mg
|
|
Hemoglobin A 1c
|
N=158 |
N=142 |
N=154 |
N=159 |
|
Baseline Mean (%)
|
9.63 |
9.51 |
9.43 |
9.44 |
|
Final Mean
|
9.61 |
9.82 |
7.92 |
7.91 |
|
Difference from Glyburide
|
|
|
-1.69 a |
-1.70 a |
|
Difference from Metformin
|
|
|
-1.90 a |
-1.91 a |
|
Fasting Plasma Glucose
|
N=163 |
N=152 |
N=160 |
N=160 |
|
Baseline Mean(mg/dL)
|
218.4 |
213.4 |
212.2 |
210.2 |
|
Final Mean
|
221.0 |
233.8 |
169.6 |
161.1 |
|
Difference from Glyburide
|
|
|
-51.3 a |
-59.9 a |
|
Difference from Metformin
|
|
|
-64.2 a |
-72.7 a |
|
Body Weight Mean
Change from Baseline
|
+ 0.43 kg |
-2.76 kg |
+ 0.75 kg |
+ 0.47 kg |
|
Final HbA 1c Distribution (%)
|
N=158 |
N=142 |
N=154 |
N=159 |
|
< 7%
|
2.5% |
2.8% |
24.7% |
22.6% |
|
≥7% and < 8%
|
9.5% |
11.3% |
33.1% |
37.1% |
|
≥8%
|
88% |
85.9% |
42.2% |
40.3% |
|
a p < 0.001
|
After 16 weeks, there was no significant
change in the mean HbA 1c
in the patients randomized to glyburide
or to metformin therapy.
Treatment with GLUCOVANCE at doses up to 20 mg/2000 mg
per day resulted in significant
lowering of HbA 1c , FPG, and PPG from baseline
compared to glyburide or
metformin alone.
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