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 Type 2 diabetes 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 2C9 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 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in 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.
Special Populations
Geriatric
Comparison of glimepiride pharmacokinetics in Type 2 diabetic 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
The pharmacokinetics of glimepiride (1 mg) were evaluated in a single dose study conducted in 30 Type 2 diabetic patients (Male = 7; Female = 23) between ages 10 and 17 years. The mean AUC(0-last)(338.8�203.1 ng�hr/mL), Cmax (102.4�47.7 ng/mL) and T1/2(3.1�1.7 hours) were comparable to those previously reported in adults (AUC(0-last) 315.2�95.9 ng�hr/mL, Cmax 103.2�34.3 ng/mL and T1/2 5.3�4.1 hours).
Gender
There were no differences between males and females in the pharmacokinetics 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 Amaryl (glimepiride tablets) in patients with Type 2 diabetes, 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. Amaryl (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). Amaryl 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 (T1/2) 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 Type 2 diabetic patients with renal impairment using doses ranging from 1-8 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 Amaryl may be given to Type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels.
Hepatic Impairment
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.
Most important information about Amaryl
More information about AMARYL (Glimepiride):
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Tags: Amaryl (Glimepiride), Conditions & Treatments, Medications, Type 2 Diabetes