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
Riomet Pharmacology, Pharmacokinetics, Studies, Metabolism - Metformin Hcl
Riomet Pharmacology, Pharmacokinetics, Studies, Metabolism - Metformin Hcl
CLINICAL PHARMACOLOGY
Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose
tolerance in patients with type 2 diabetes, lowering both basal and postprandial
plasma glucose. Its pharmacologic mechanisms of action are different from other
classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose
production, decreases intestinal absorption of glucose, and improves insulin
sensitivity by increasing peripheral glucose uptake and utilization. Unlike
sulfonylureas, metformin does not produce hypoglycemia in either patients with
type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS)
and does not cause hyperinsulinemia. With metformin therapy, insulin secretion
remains unchanged while fasting insulin levels and day-long plasma insulin response
may actually decrease.
Pharmacokinetics
Absorption and Bioavailability
Two pharmacokinetic studies have been performed in healthy
volunteers to evaluate the bioavailability of RIOMET in comparison with
the commercially available metformin tablets under fasting and fed conditions
(study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects
of food on absorption of RIOMET.
The rate and extent of absorption of RIOMET was found to be
comparable to that of Metformin tablets under fasting or fed conditions (see
Table 1).
|
Table 1. Select Mean (±
S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg
RIOMET and Metformin tablets in healthy, nondiabetic adults (n= 36) under
fed and fasting conditions
|
|
Formulation
|
Cmax (ng/mL)
|
AUC0-¥
(ng.h/mL)
|
tmax (h)
|
|
Study 1- Fasting state
|
|
RIOMET
|
1540.1 ± 451.1
|
9069.6 + 2593.6
|
2.2 + 0.5
|
|
Metformin Tablets
|
1885.1+498.5
|
11100.1 + 2733.1
|
2.5+0.6
|
|
T/R Ratio X 100 (90% confidence interval)
|
81.2 (76.3-86.4)
|
81.2 (76.9-85.6)
|
-
|
|
Study 2- Fed State
|
|
RIOMET
|
1235.3 + 177.7
|
8950.1+1381.2
|
4.1+0.8
|
|
Metformin Tablets
|
1361+ 298.8
|
9307.7+ 1839.8
|
3.7+ 0.8
|
|
T/R Ratio X 100 (90% confidence interval)
|
91.8 (87.4-96.5)
|
97.0 (92.9-101.2)
|
-
|
|
T-test product (RIOMET)
|
|
R-reference product (metformin tablets)
|
The food-effect study (study 3) assessed the effects of a high
fat/high calorie meal and a low fat/low calorie meal on the bioavailability
of RIOMET in comparison with administration in the fasted state, in healthy
volunteers. The extent of absorption was increased by 21% and 17% with the low
fat/low calorie meal and the high fat/high calorie meal, respectively, compared
with the administration in the fasted state. The rate and extent of absorption
with high fat/high calorie and low fat/ low calorie meal were similar.
The mean tmax was 2.5 hours under fasting conditions as compared to 3.9
hours with both low fat/ low calorie meal and high fat/high calorie meals (see
Table 2).
|
Table 2. Select Mean (±
S.D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses
of 1000 mg RIOMET in healthy, nondiabetic adults (n= 33) under fed (high
fat/high calorie meal and low fat/low calorie meal) and fasting conditions
(study 3)
|
|
Meal type
|
Cmax(ng/mL)
|
AUC0-¥
ng.h/mL)
|
tmax (h)
|
|
Fasting (F)
|
1641.5 ± 551.8
|
9982.9 ± 2544.5
|
2.5 ± 0.9
|
|
Low fat/ low calorie meal (L)
|
1525.8 ± 396.7
|
11542.0± 2947.5
|
3.9± 0.6
|
|
High fat/high calorie meal (H)
|
1432.5 ± 346.8
|
11184.5± 2446.1
|
3.9 ± 0.8
|
|
L/F Ratio X 100 (90% confidence interval)
|
94.6 (84.0-106.5)
|
115.6 (103.6-128.9)
|
-
|
|
H/F Ratio X 100 (90% confidence interval)
|
89.4 (79.4-100.6)
|
112.6 (100.9-125.6)
|
-
|
|
L/H Ratio X 100 (90% confidence interval)
|
105.8 (94.0-119.2)
|
102.7 (92.0-114.6)
|
-
|
Studies using single oral doses of metformin tablet formulations
500 mg to 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.
Distribution
The apparent volume of distribution (V/F) of metformin following
single oral doses of a 850 mg tablet averaged 654±358 L. Metformin is negligibly
bound to plasma proteins, in contrast to sulfonylureas, which are more than
90% protein bound. Metformin partitions into erythrocytes, most likely as a
function of time. At usual clinical doses and dosing schedules of metformin,
steady state plasma concentrations are reached within 24-48 hours and are generally
< 1 g/mL. During controlled clinical trials of metformin, maximum metformin
plasma levels did not exceed 5 mg/mL, even at maximum
doses.
Metabolism and Elimination
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 3) 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
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 3), nor is there
any accumulation of metformin in either group at usual clinical doses.
Renal Insufficiency
In patients with decreased renal function (based on measured
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 3; also see WARNINGS).
Hepatic Insufficiency
No pharmacokinetic studies of metformin have been conducted
in patients with hepatic insufficiency.
Geriatrics
Limited data from controlled pharmacokinetic studies of metformin
in healthy elderly subjects suggest that total plasma clearance of metformin
is decreased, the half-life is prolonged, and Cmax 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 3). RIOMET (metformin hydrochloride oral
solution) treatment should not be initiated in patients 80 years of age unless
measurement of creatinine clearance demonstrates that renal function is not
reduced. (See WARNINGS and DOSAGE
AND ADMINISTRATION.)
|
Table 3. Select Mean (±
S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple
Oral Doses of Metformin
|
|
Subject Groups: Metformin dosea (number of
subjects)
|
Cmaxb (mg/mL)
|
Tmaxc (hrs)
|
Renal Clearance (mL/min)
|
|
Healthy, nondiabetic adults:
|
|
|
|
|
500 mg single dose (24)
|
1.03+(0.33)
|
2.75±(0.81)
|
600± (132)
|
|
850 mg single dose (74)d
|
1.60± (0.38)
|
2.64±(0.82)
|
552 ± (139)
|
|
850 mg three times daily for 19 dosese (9)
|
2.01± (0.42)
|
1.79±(0.94)
|
642± (173)
|
|
Adults with type 2 diabetes:
|
|
|
|
|
850 mg single dose (23)
|
1.48± (0.5)
|
3.32±(1.08)
|
491 ± (138)
|
|
850 mg three times daily for 19 dosese (9)
|
1.90± (0.62)
|
2.01±(1.22)
|
550 ± (160)
|
|
Elderlyf, healthy nondiabetic adults:
|
|
|
|
|
850 mg single dose (12)
|
2.45 ± (0.70)
|
2.71±(1.05)
|
412 ± (98)
|
|
Renally-impaired adults:
|
|
|
|
|
850 mg single dose
|
|
|
|
|
Mild (CLcrg 61-90mL/min)
(5)
|
1.86± (0.52)
|
3.20±(0.45)
|
384± (122)
|
|
Moderate (CLcr 31-60mL/min) (4)
|
4.12± (1.83)
|
3.75±(0.50)
|
108± (57)
|
|
Severe (CLcr 10-30mL/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- Combined results (average means) of five studies:
mean age 32 years (range 23-59 years)
|
|
e- Kinetic study done following dose 19, given fasting
|
|
f- Elderly subjects, mean age 71 years (range 65-81 years)
|
|
g- CLcr = creatinine clearance normalized to body surface
area of 1.73 m2
|
Pediatrics
After administration of a single oral metformin 500 mg dose
with food, geometric mean metformin Cmax and AUC differed less than 5% between
pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched
healthy adults (20 to 45 years of age), all with normal renal function.
Gender
Metformin pharmacokinetic parameters did not differ significantly
between normal subjects and patients with 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 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
In a double-blind, placebo-controlled, multicenter U.S. clinical
trial involving obese patients with type 2 diabetes whose hyperglycemia was
not adequately controlled with dietary management alone (baseline fasting plasma
glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2550
mg/day) for 29 weeks resulted in significant mean net reductions in fasting
and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c)
of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group
(see Table 4).
|
Table 4. Metformin vs Placebo Summary of Mean Changes
from Baseline* in Fasting Plasma Glucose, HbA1c and Body Weight,
at Final Visit (29-week study)
|
|
|
Metformin (n= 141)
|
Placebo (n= 145)
|
p-Value
|
|
FPG (mg/ dL)
|
|
|
|
|
Baseline
|
241.5
|
237.7
|
NS**
|
|
Change at Final Visit
|
-53.0
|
6.3
|
0.001
|
|
Hemoglobin A1c (%)
|
|
|
|
|
Baseline
|
8.4
|
8.2
|
NS**
|
|
Change at Final Visit
|
-1.4
|
0.4
|
0.001
|
|
Body Weight (lbs)
|
|
|
|
|
Baseline
|
201.0
|
206.0
|
NS**
|
|
Change at Final Visit
|
-1.4
|
-2.4
|
NS**
|
|
*-All patients on diet therapy at Baseline
|
|
**-Not statistically significant
|
A 29-week, double-blind, placebo-controlled study of metformin
and glyburide, alone and in combination, was conducted in obese patients with
type 2 diabetes who had failed to achieve adequate glycemic control while on
maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table
5). Patients randomized to the combination arm started therapy with metformin
500 mg and glyburide 20 mg. At the end of each week of the first four weeks
of the trial, these patients had their dosages of metformin increased by 500
mg if they had failed to reach target fasting plasma glucose.
After week four, such dosage adjustments were made monthly,
although no patient was allowed to exceed metformin 2500 mg. Patients in the
metformin only arm (metformin plus placebo) followed the same titration schedule.
At the end of the trial, approximately 70% of the patients in the combination
group were taking metformin 2000 mg/glyburide 20 mg or metformin 2500 mg/glyburide
20 mg. Patients randomized to continue on glyburide experienced worsening of
glycemic control, with mean increases in FPG, PPG, and HbA1c of 14
mg/dL, 3 mg/dL and 0.2%, respectively. In contrast, those randomized to metformin
(up to 2500 mg/day) experienced a slight improvement, with mean reductions in
FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL and 0.4%, respectively. The combination
of metformin and glyburide was effective in reducing FPG, PPG, and HbA1c levels
by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide
treatment alone, the net differences with combination treatment were -77 mg/dL,
-68 mg/dL and -1.9%, respectively (see Table 5).
|
Table 5. Combined Metformin/ Glyburide (Comb) vs Glyburide
(Glyb) or Metformin (Met) Monotherapy: Summary of Mean Changes from Baseline*
in Fasting Plasma Glucose, HbA1c and Body Weight, at Final Visit (29-week
study)
|
|
|
Comb (n= 213)
|
Glyb (n= 209)
|
Met (n=210)
|
Glyb vs Comb
|
p-values Met vs Comb
|
Met vs Glyb
|
|
Fasting Plasma Glucose (mg/ dL)
|
|
Baseline
|
250.5
|
247.5
|
253.9
|
NS**
|
NS**
|
NS**
|
|
Change at Final Visit
|
-63.5
|
13.7
|
-0.9
|
0.001
|
0.001
|
0.025
|
|
Hemoglobin A1c (%)
|
|
Baseline
|
8.8
|
8.5
|
8.9
|
NS**
|
NS**
|
0.007
|
|
Change at Final Visit
|
-1.7
|
0.2
|
-0.4
|
0.001
|
0.001
|
0.001
|
|
Body Weight (lbs)
|
|
Baseline
|
202.2
|
203.0
|
204.0
|
NS**
|
NS**
|
NS**
|
|
Change at Final Visit
|
0.9
|
-0.7
|
-8.4
|
0.011
|
0.001
|
0.001
|
|
*- ALL PATIENTS ON GLYBURIDE, 20 MG /DAY, AT BASELINE;
|
|
**-NOT STATISTICALLY SIGNIFICANT
|
The magnitude of the decline in fasting blood glucose concentration
following the institution of metformin therapy was proportional to the level
of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting
glucose concentrations experienced greater declines in plasma glucose and glycosylated
hemoglobin.
In clinical studies, metformin, alone or in combination with
a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol,
and LDL cholesterol levels and had no adverse effects on other lipid levels
(see Table 6).
|
Table 6. Summary of Mean Percent Change from Baseline
of Major Serum Lipid Variables at Final Visit (29-week studies)
|
|
|
Metformin vs Placebo
|
Combined Metformin/ Glyburide vs Monotherapy
|
|
|
Metformin (n= 141)
|
Placebo (n= 145)
|
Metformin (n= 210)
|
Metformin/ Glyburide (n=213)
|
Glyburide
(n= 209)
|
|
Total Cholesterol (mg/dL)
|
|
Baseline
|
211.0
|
212.3
|
213.1
|
215.6
|
219.6
|
|
Mean % change at Final Visit
|
-5%
|
1%
|
-2%
|
-4%
|
1%
|
| |
|
|
|
|
|
Total Triglycerides (mg/dL)
|
|
Baseline
|
236.1
|
203.5
|
242.5
|
215.0
|
266.1
|
|
Mean % change at Final Visit
|
-16%
|
1%
|
-3%
|
-8%
|
4%
|
|
LDL-Cholesterol (mg/dL)
|
|
Baseline
|
135.4
|
138.5
|
134.3
|
136.0
|
137.5
|
|
Mean % change at Final Visit
|
-8%
|
1%
|
-4%
|
-6%
|
3%
|
|
HDL-Cholesterol (mg/dL)
|
|
Baseline
|
39.0
|
40.5
|
37.2
|
39.0
|
37.0
|
|
Mean % change at Final Visit
|
2%
|
-1%
|
5%
|
3%
|
1%
|
In contrast to sulfonylureas, body weight of individuals on
metformin tended to remain stable or even decrease somewhat (see Tables 4
and 5).
A 24-week, double-blind, placebo-controlled study of metformin
plus insulin versus insulin plus placebo was conducted in patients with type
2 diabetes who failed to achieve adequate glycemic control on insulin alone
(see Table 7). Patients randomized to receive metformin plus insulin
achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction
in HbA1c achieved by insulin plus placebo. The improvement in glycemic
control was achieved at the final study visit with 16% less insulin, 93.0 U/day
vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively,
p=0.04.
|
Table 7. Combined Metformin/ Insulin vs Placebo/ Insulin
Summary of Mean Changes from Baseline in HbA1c and Daily Insulin
Dose
|
|
|
Metformin/ Insulin (n= 26)
|
Placebo/ Insulin (n= 28)
|
Treatment difference Mean +SE
|
|
Hemoglobin A1c (%)
|
|
Baseline
|
8.95
|
9.32
|
|
|
|
Change at Final Visit
|
-2.10
|
-1.56
|
-0.54
|
0.43a
|
|
Insulin Dose (U/day)
|
|
Baseline
|
93.12
|
94.64
|
|
|
|
Change at Final Visit
|
-0.15
|
15.93
|
-16.08
|
7.77b
|
|
A-STATISTICALLY SIGNIFICANT USING ANALYSIS OF COVARIANCE
WITH BASELINE AS COVARIATE (P=0.04). NOT SIGNIFICANT USING ANALYSIS OF
VARIANCE (VALUES SHOWN IN TABLE)
|
|
B- STATISTICALLY SIGNIFICANT FOR INSULIN (P= 0.04)
|
A second double-blind, placebo-controlled study (n=51), with
16 weeks of randomized treatment, demonstrated that in patients with type 2
diabetes controlled on insulin for 8 weeks with an average HbA1c
of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control
(HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin
and placebo plus insulin, respectively) with 19% less insulin versus baseline
(reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin
plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated
that the combination of metformin plus insulin resulted in reduction in body
weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo
plus insulin, p=0.01.
Pediatric Clinical Studies
In a double-blind, placebo-controlled study in pediatric patients
aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with
metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment
11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL,
compared with placebo (see Table 8).
|
Table 8. Metformin vs Placebo (Pediatricsa)
Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight
at Final Visit
|
| |
Metformin
|
Placebo
|
p-value
|
|
FPG (mg/dL)
|
(n= 37)
|
(n= 36)
|
<0.001
|
|
Baseline
|
162.4
|
192.3
|
|
|
Change at Final Visit
|
-42.9
|
21.4
|
|
|
Body Weight (lbs)
|
(n= 39)
|
(n= 38)
|
NS**
|
|
Baseline
|
205.3
|
189.0
|
|
|
Change at Final Visit
|
-3.3
|
-2.0
|
|
|
a-Pediatric patients mean age 13.8 years (range 10-16
years)
|
|
*- All patients on diet therapy at Baseline
|
|
**-Not statistically significant
|
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