CLINICAL PHARMACOLOGY
Mechanism of Action
Glipizide/Metformin HCl tablets combines two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Glipizide 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. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment.
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
Glipizide/Metformin HCl tablets
In a single-dose study in healthy subjects, the glipizide and metformin components of Glipizide/Metformin HCl tablets 5 mg/500 mg were bioequivalent to coadministered GLUCOTROL® (glipizide) and GLUCOPHAGE® (metformin hydrochloride tablets). Following administration of a single Glipizide/Metformin HCl tablets 5 mg/500 mg in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (Cmax) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (Tmax) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. Cmax for the metformin component was reduced approximately 14% by food whereas AUC was not affected. Tmax for the metformin component was delayed 1 hour after food.
Glipizide
Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.
Metformin Hydrochloride
The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 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
Glipizide
Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labeled drug.
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 to 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
Glipizide
The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant.
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
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
The metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see PRECAUTIONS). No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for metformin.
Renal Insufficiency
The metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see PRECAUTIONS).
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 glipizide 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 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 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 Dosea
(Number of Subjects) | Cmaxb
(µg/mL) | Tmaxc
(hrs) | Renal Clearance
(mL/min) |
|---|
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 CLcr = creatinine clearance normalized to body surface area of 1.73 m2 |
Healthy, Nondiabetic Adults:
500 mg SDd (24)
850 mg SD (74)e
850 mg t.i.d. for 19 dosesf (9) |
1.03 (±0.33)
1.60 (±0.38)
2.01 (±0.42) |
2.75 (±0.81)
2.64 (±0.82)
1.79 (±0.94) |
600 (±132)
552 (±139)
642 (±173) |
Adults with Type 2 Diabetes:
850 mg SD (23)
850 mg t.i.d. for 19 dosesf (9) |
1.48 (±0.5)
1.90 (±0.62) |
3.32 (±1.08)
2.01 (±1.22) |
491 (±138)
550 (±160) |
Elderlyg, Healthy Nondiabetic Adults:
850 mg SD (12) |
2.45 (±0.70) |
2.71 (±1.05) |
412 (±98) |
Renal-impaired Adults: 850 mg SD
Mild (CLcrh 61-90 mL/min) (5)
Moderate (CLcr 31-60 mL/min) (4)
Severe (CLcr 10-30 mL/min) (6) |
1.86 (±0.52)
4.12 (±1.83)
3.93 (±0.92) |
3.20 (±0.45)
3.75 (±0.50)
4.01 (±1.10) |
384 (±122)
108 (±57)
130 (±90) |
Pediatrics
No data from pharmacokinetic studies in pediatric subjects are available for glipizide. After administration of a single oral Metformin hydrochloride 500 mg tablet 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
There is no information on the effect of gender on the pharmacokinetics of glipizide.
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 glipizide.
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).
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