Glimepiride pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Pharmacodynamics Absorption Distribution Metabolism Excretion Pharmacokinetic parameters Variability Special populations
 * Geriatric
 * Pediatric
 * Gender
 * Race
 * Renal insufficiency
 * Hepatic insufficiency
 * Other populations

Mechanism
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. Return to top

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 2) 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 Glimepiride. 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 tablets 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 Type 2 diabetic 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 2 1/2 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 Type 2 diabetes. Return to top

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). Return to top

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%. Return to top

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 P4502C9 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. Return to top

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 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. Return to top

Pharmacokinetic parameters
Data indicate that Glimepiride did not accumulate in serum, and the pharmacokinetics of Glimepiride were not different in healthy volunteers and in Type 2 diabetic patients. Oral clearance of Glimepiride did not change over the 1 to 8 mg dose range, indicating linear pharmacokinetics. Return to top

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. Return to top

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. Return to top

Pediatric
Pharmacokinetics information for pediatric patients is approved for Sanofi-Aventis US’ Amaryl® (Glimepiride oral tablets). However, due to Sanofi-Aventis US’ marketing exclusivity rights this drug product is not labeled for pediatric use. Return to top

Gender
There were no differences between males and females in the pharmacokinetics of Glimepiride when adjustment was made for differences in body weight. Return to top

Race
No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of Glimepiride tablets in patients with Type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63). Return to top

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 (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 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 Type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels. Return to top

Hepatic insufficiency
No studies were performed in patients with hepatic insufficiency. Return to top

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. Return to top