CLINICAL PHARMACOLOGY
Mechanism of Action
The primary mechanism of action of glimepiride
in lowering blood glucose appears to be dependent on stimulating
the release of insulin from functioning pancreatic beta
cells. In addition, extrapancreatic effects may also play
a role in the activity of sulfonylureas such as glimepiride.
This is supported by both preclinical and clinical studies
demonstrating that glimepiride administration can lead to
increased sensitivity of peripheral tissues to insulin.
These findings are consistent with the results of a long-term,
randomized, placebo-controlled trial in which glimepiride
therapy improved postprandial insulin/C-peptide responses
and overall glycemic control without producing clinically
meaningful increases in fasting insulin/C-peptide levels.
However, as with other sulfonylureas, the mechanism by which
glimepiride lowers blood glucose during long-term administration
has not been clearly established.
Glimepiride is effective as initial drug therapy. In patients
where monotherapy with glimepiride or metformin has not
produced adequate glycemic control, the combination of glimepiride
and metformin may have a synergistic effect, since both
agents act to improve glucose tolerance by different primary
mechanisms of action. This complementary effect has been
observed with metformin and other sulfonylureas, in multiple
studies.
Pharmacodynamics
A mild glucose-lowering effect first appeared following
single oral doses as low as 0.5 to 0.6 mg in healthy subjects.
The time required to reach the maximum effect (i.e., minimum
blood glucose level [Tmin]) was about 2 to 3 hours. In noninsulin-dependent
(Type II) diabetes mellitus (NIDDM) patients, both fasting
and 2-hour postprandial glucose levels were significantly
lower with glimepiride (1, 2, 4, and 8 mg once daily) than
with placebo after 14 days of oral dosing. The glucose-lowering
effect in all active treatment groups was maintained over
24 hours.
In larger dose-ranging studies, blood glucose and HbA1c
were found to respond in a dose-dependent manner over the
range of 1 to 4 mg/day of gilmepiride. Some patients, particularly
those with higher fasting plasma glucose (FPG) levels, may
benefit from doses of glimepiride up to 8 mg once daily.
No difference in response was found when glimepiride was
administered once or twice daily.
In two 14-week, placebo-controlled studies in 720 subjects,
the average net reduction in HbA1c for glimepiride tablet
patients treated with 8 mg once daily was 2% in absolute
units compared with placebo-treated patients. In a long-term,
randomized, placebo-controlled study of NIDDM patients unresponsive
to dietary management, glimepiride therapy improved postprandial
insulin/C-peptide responses, and 75% of patients achieved
and maintained control of blood glucose and HbA1c. Efficacy
results were not affected by age, gender, weight, or race.
In long-term extension trials with previously-treated patients,
no meaningful deterioration in mean fasting blood glucose
(FBG) or HbA1c levels was seen after 2½ years of
glimepiride therapy.
Combination therapy with glimepiride and insulin (70% NPH/30%
regular) was compared to placebo/insulin in secondary failure
patients whose body weight was >130% of their ideal body
weight. Initially, 5 to 10 units of insulin were administered
with the main evening meal and titrated upward weekly to
achieve predefined FPG values. Both groups in this double-blind
study achieved similar reductions in FPG levels but the
glimepiride/insulin therapy group used approximately 38%
less insulin.
Glimepiride therapy is effective in controlling blood glucose
without deleterious changes in the plasma lipoprotein profiles
of patients treated for NIDDM.
Pharmacokinetics
Absorption: After oral administration, glimepiride
is completely (100%) absorbed from the GI tract. Studies
with single oral doses in normal subjects and with multiple
oral doses in patients with NIDDM have shown significant
absorption of glimepiride within 1 hour after administration
and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride
was given with meals, the mean Tmax (time to reach Cmax)
was slightly increased (12%) and the mean Cmax and AUC (area
under the curve) were slightly decreased (8% and 9%, respectively).
Distribution: After intravenous (IV) dosing
in normal subjects, the volume of distribution (Vd) was
8.8 L (113 ml/kg), and the total body clearance (CL) was
47.8 ml/min. Protein binding was greater than 99.5%.
Metabolism: Glimepiride is completely
metabolized by oxidative biotransformation after either
an IV or oral dose. The major metabolites are the cyclohexyl
hydroxy methyl derivative (M1) and the carboxyl derivative
(M2). Cytochrome P450 II C9 has been shown to be involved
in the biotransformation of glimepiride to M1. M1 is further
metabolized to M2 by one or several cytosolic enzymes. M1,
but not M2, possesses about 1/3 of the pharmacological activity
as compared to its parent in an animal model; however, whether
the glucose-lowering effect of M1 is clinically meaningful
is not clear.
Excretion: When 14C-glimepiride was given
orally, approximately 60% of the total radioactivity was
recovered in the urine in 7 days and M1 (predominant) and
M2 accounted for 80% to 90% of that recovered in the urine.
Approximately 40% of the total radioactivity was recovered
in the feces and M1 and M2 (predominant) accounted for about
70% of that recovered in feces. No parent drug was recovered
from urine or feces. After IV dosing in patients, no significant
biliary excretion of glimepiride or its M1 metabolite has
been observed.
Pharmacokinetic Parameters:
The pharmacokinetic parameters of glimepiride obtained from
a single-dose, crossover, dose-proportionality (1, 2, 4,
and 8 mg) study in normal subjects and from a single- and
multiple-dose, parallel, dose-proportionality (4 and 8 mg)
study in patients with NIDDM are summarized in TABLE 1.
| TABLE 1 |
| |
Volunteers |
Patients with
NIDDM |
| |
Single Dose |
Single Dose (Day 1) |
Multiple Dose (Day 10) |
| |
Mean ±SD |
Mean ±SD |
Mean ±SD |
| |
|
|
|
| |
103 ±
34 (12) |
¾ |
¾ |
| |
177 ±
44 (12) |
¾ |
¾ |
| |
308 ±
69 (12) |
352 ±
222 (12) |
309 ±
134 (12) |
| |
557±
152 (12) |
591 ±
232 (14) |
578 ±
265 (11) |
| |
2.4 ±
0.8 (48) |
2.5 ±
1.2 (26) |
2.8 ±
2.2 (23) |
| |
52.1 ±
16.0 (48) |
48.5 ±
29.3 (26) |
52.7 ±
40.3 (23) |
| |
21.8 ±
13.9 (48) |
19.8 ±
12.7 (26) |
37.1 ±
18.2 (23) |
| |
5.35 ±
4.1 (48) |
5.0 ±
2.5 (26) |
9.2 ±
3.6 (23) |
| ()= No.
of subjects. |
| CL/f=
Total body clearance after oral dosing. |
| Vd/f=
Volume of distribution calculated after oral dosing. |
These data indicate that glimepiride did not accumulate
in serum, and the pharmacokinetics of glimepiride were not
different in healthy volunteers and in NIDDM patients. Oral
clearance of glimepiride did not change over the 1 to 8
mg dose range, indicating linear pharmacokinetics.
Variability: In normal healthy volunteers,
the intra-individual variabilities of Cmax, AUC, and CL/f
for glimepiride were 23%, 17%, and 15%, respectively, and
the inter-individual variabilities were 25%, 29%, and 24%,
respectively.
Special Populations
Geriatric: Comparison of glimepiride
pharmacokinetics in NIDDM patients £65 years and those
>65 years was performed in a study using a dosing regimen
of 6 mg daily. There were no significant differences in
glimepiride pharmacokinetics between the two age groups.
The mean AUC at steady state for the older patients was
about 13% lower than that for the younger patients; the
mean weight-adjusted clearance for the older patients was
about 11% higher than that for the younger patients.
Pediatric: No studies were performed in
pediatric patients.
Gender: There were no differences between
males and females in the pharmcokinetics of glimepiride
when adjustment was made for differences in body weight.
Race: No pharmacokinetic studies to assess
the effects of race have been performed, but in placebo-controlled
studies of glimepiride tablets in patients with NIDDM, the
antihyperglycemic effect was comparable in whites (n=536),
blacks (n=63), and Hispanics (n=63).
Renal Insufficiency: A single-dose, open-label
study was conducted in 15 patients with renal impairment.
Glimepiride (3 mg) was administered to 3 groups of patients
with different levels of mean creatinine clearance (CLcr);
(Group I, CLcr=77.7 ml/min, n=5), (Group II, CLcr=27.7 ml/min,
n=3), and (Group III, CLcr=9.4 ml/min, n=7). Glimepiride
was found to be well tolerated in all 3 groups. The results
showed that glimepiride serum levels decreased as renal
function decreased. However, M1 and M2 serum levels (mean
AUC values) increased 2.3 and 8.6 times from Group I to
Group III. The apparent terminal half-life (T½) for
glimepiride did not change, while the half-lives for M1
and M2 increased as renal function decreased. Mean urinary
excretion of M1 plus M2 as percent of dose, however, decreased
(44.4%, 21.9%, and 9.3% for Groups I to III).
A multiple-dose titration study was also conducted in 16
NIDDM patients with renal impairment using doses ranging
from 1 to 8 mg daily for 3 months. The results were consistent
with those observed after single doses. All patients with
a CLcr less than 22 ml/min had adequate control of their
glucose levels with a dosage regimen of only 1 mg daily.
The results from this study suggested that a starting dose
of 1 mg glimepiride may be given to NIDDM patients with
kidney disease, and the dose may be titrated based on fasting
blood glucose levels.
Hepatic Insufficiency: No studies were
performed in patients with hepatic insufficiency.
Other Populations: There were no important
differences in glimepiride metabolism in subjects identified
as phenotypically different drug-metabolizers by their metabolism
of sparteine.
The pharmacokinetics of glimepiride in morbidly obese patients
were similar to those in the normal weight group, except
for a lower Cmax and AUC. However, since neither Cmax nor
AUC values were normalized for body surface area, the lower
values of Cmax and AUC for the obese patients were likely
the result of their excess weight and not due to a difference
in the kinetics of glimepiride.
Drug Interactions
The hypoglycemic action of sulfonylureas may be
potentiated by certain drugs, including nonsteroidal anti-inflammatory
drugs and other drugs that are highly protein bound, such
as salicylates, sulfonamides, chloramphenicol, coumarins,
probenecid, monamine oxidase inhibitors, and beta adrenergic
blocking agents. When these drugs are administered to a
patient receiving glimepiride, the patient should be observed
closely for hypoglycemia. When these drugs are withdrawn
from a patient receiving glimepiride, the patient should
be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead
to loss of control. These drugs include the thiazides and
other diurectics, corticosteroids, phenothiazines, thyroid
products, estrogens, oral contraceptives, phenytoin, nicotinic
acid, sympathomimetics, and isoniazid. When these drugs
are administered to a patient receiving glimepiride, the
patient should be closely observed for loss of control.
When these drugs are withdrawn from a patient receiving
glimepiride, the patient should be observed closely for
hypoglycemia.
Coadministration of aspirin (1 g tid) and glimepiride led
to a 34% decrease in the mean glimepiride AUC and, therefore,
a 34% increase in the mean CL/f. The mean Cmax had a decrease
of 4%. Blood glucose and serum C-peptide concentrations
were unaffected and no hypoglycemic symptoms were reported.
Pooled data from clinical trials showed no evidence of clinically
significant adverse interactions with uncontrolled concurrent
administration of aspirin and other salicylates.
Coadministration of either cimetidine (800 mg once daily)
or ranitidine (150 mg bid) with a single 4-mg oral dose
of glimepiride did not significantly alter the absorption
and disposition of glimepiride, and no differences were
seen in hypoglycemic symptomatology. Pooled data from clinical
trials showed no evidence of clinically significant adverse
interactions with uncontrolled concurrent administration
of H2-receptor antagonists.
Concomitant administration of propranolol (40 mg tid) and
glimepiride significantly increased Cmax, AUC, and T½
of glimepiride by 23%, 22%, and 15%, respectively, and it
decreased CL/f by 18%. The recovery of M1 and M2 from urine,
however, did not change. The pharmacodynamic responses to
glimepiride were nearly identical in normal subjects receiving
propranolol and placebo. Pooled data from clinical trials
in patients with NIDDM showed no evidence of clinically
significant adverse interactions with uncontrolled concrurrent
administration of beta-blockers. However, if beta blockers
are used, caution should be exercised and patients should
be warned about the potential for hypoglycemia.
Concomitant administration of glimepiride tablets(4 mg once
daily) did not alter the pharmacokinetic characteristics
of R- and S-warfarin enantiomers following administration
of a single dose (25 mg) of racemic warfarin to healthy
subjects. No changes were observed in warfarin plasma protein
binding. Glimepiride treatment did result in a slight, but
statistically significant, decrease in the pharmacodynamic
response to warfarin. The reductions in mean area under
the prothrombin time (PT) curve and maximum PT values during
glimepiride treatment were very small (3.3% and 9.9%, respectively)
and are unlikely to be clinically important.
The responses of serum glucose, insulin, C-peptide, and
plasma glucagon to 2 mg glimepiride were unaffected by coadministration
of ramipril (an ACE inhibitor) 5 mg once daily in normal
subjects. No hypoglycemic symptoms were reported. Pooled
data from clinical trials in patients with NIDDM showed
no evidence of clinically significant adverse interactions
with uncontrolled concurrent administration of ACE inhibitors.
A potential interaction between oral miconazole and oral
hypoglycemic agents leading to severe hypoglycemia has been
reported. Whether this interaction also occurs with the
intravenous, topical, or vaginal preparations of miconazole
is not known. Potential interactions of glimepiride with
other drugs metabolized by cytochrome P450 II C9 also include
phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic
acid.
Although no specific interaction studies were performed,
pooled data from clinical trials showed no evidence of clinically
significant adverse interactions with uncontrolled concurrent
administration of calcium-channel blockers, estrogens, fibrates,
NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid
hormone.
CLINICAL STUDIES
Ophthalmic examinations were carried out in over 500 subjects
during long-term studies using the methodology of Taylor
and West and Laties et al. No significant differences were
seen between glimepiride and glyburide in the number of
subjects with clinically important changes in visual acuity,
intraocular tension, or in any of the five lens-related
variables examined.
Ophthalmic examinations were carried out during long-term
studies using the method of Chylack et al. No significant
or clinically meaningful differences were seen between glimepiride
and glipizide with respect to cataract progression by subjective
LOCS II grading and objective image analysis systems, visual
acuity, intraocular pressure, and general ophthalmic examination.
ANIMAL PHARMACOLOGY
Reduced serum glucose values and degranulation of the pancreatic
beta cells were observed in beagle dogs exposed to 320 mg
glimepiride/kg/day for 12 months (approximately 1000 times
the recommended human dose based on surface area). No evidence
of tumor formation was observed in any organ. One female
and one male dog developed bilateral subscapsular cataracts.
Non-GLP studies indicated that glimepiride was unlikely
to exacerbate cataract formation. Evaluation of the co-cataractogenic
potential of glimepiride in several diabetic and cataract
rat models was negative and there was no adverse effect
of glimepiride on bovine ocular lens metabolism in organ
culture.
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