Amaryl Mechanism of Action



PT. Aventis Pharma
Full Prescribing Info
Pharmacology: Pharmacodynamics: Mode of Action: Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentrations. The primary mechanism of action of glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic β cells. Glimepiride acts in concert with glucose by improving the sensitivity of β cells to physiological glucose stimulus, resulting in insulin secretion in the rhythm of meals. In addition, extrapancreatic effects (e.g., reduction of basal hepatic glucose production and increased peripheral tissue sensitivity to insulin and glucose uptake) may also play a limited role in the activity of glimepiride.
In non-fasting diabetic patients, the hypoglycaemic action of a single dose of glimepiride persist for 24 hours. Evidence from in vitro and animal studies suggests that there is lower glucagon secretion with glimepiride than glibenclamide and this may give rise to a prolonged reduction of blood glucose levels without increased plasma insulin levels. The clinical significance of these findings is yet to be clarified. A long-term, randomized, placebo-controlled clinical trial demonstrated that Amaryl therapy improves postprandial insulin/C-peptide responses and overall glycaemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels.
The efficacy of Amaryl is not affected by age, gender or weight. Amaryl therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profile in patients. The physiological response to acute exercise (ie, reduction of insulin secretion) is still present during glimepiride therapy.
Pharmacokinetics: Absorption: Glimepiride is completely absorbed after oral administration. The peak serum concentration (Cmax) is reached in about 2.5 hours. There is a linear relationship between dose and both Cmax and AUC (area under the plasma concentration-time curve). Food does not significantly affect the rate or extent of absorption of glimepiride.
Distribution: After intravenous dosing in normal subjects, the volume of distribution was 8.8 litres (113 mL/kg) and the total body clearance was greater than 99%. Glimepiride is likely to be only minimally removed by hemodialysis due to its high protein binding. Multiple-dose studies with glimepiride in diabetic patients demonstrated plasma-concentration time curves similar to single dose studies, indicating that there is no accumulation of drug in tissue depots.
Metabolism and excretion: The elimination half-life of glimepiride at steady state is about 5 to 8 hours after oral administration. However, result of pharmacokinetics study on patients with type 2 diabetes mellitus indicated that higher doses may be associated with a longer half-life.
Glimepiride is completely metabolized by oxidative biotransformation. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). In vitro studies indicate that cytochrome P450 2C9 is the principal enzyme involved in a biotransformation of glimepiride to M1. M1 has been found to have about 40% of pharmacological activity of glimepiride. It is eliminated via the urine and also by further metabolism to M2 via one or several cytosolic enzymes. M1 has a terminal elimination half-life of 3-6 hours after an oral dose. The formation of M1 is linear up to a dose of 16 mg glimepiride. The kinetics of M2 have not been fully elucidated due to low plasma levels. Its terminal elimination half-life after an oral dose is about 5-6 hours.
Following an oral dose of glimepiride, 35 % of the dose is excreted in faeces and 58 % in urine.
Special Population: Gender: Pharmacokinetics of glimepiride are similar in males and females.
Elderly: Pharmacokinetics of glimepiride are similar in young and elderly (>65 years) patients. Intra-individual variability is low.
Hepatic impairment: The effects of hepatic failure on the clearance of glimepiride have not been systematically examined.
Renal impairment: In a single-dose, open label study conducted in 15 patients with renal impairment, glimepiride (3 mg) was administered to three groups of patients with different levels of mean creatinine clearance (CrCl); (Group I, CrCl=77.7 mL/min, n=5), (Group II, CrCl=27.4 mL/min, n=3), (Group III, CrCl=9.4 mL/min, n=7). Glimepiride was found to be well tolerated in all three 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 II. 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 Group I to III). Result from multiple-dose titration study conducted in 16 patients with renal impairment using doses ranging from 1-8 mg daily for 3 months were consistent with the result after a single dose. All patients with a CrCl < 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The result from this study suggested that a starting dose of 1 mg AMARYL may be given to a patient with type 2 diabetes mellitus with renal disease, and the dose may be titrated based on fasting blood glucose levels (see Contraindications and Dosage & Administration).
It is not known if glimepiride is dialyzable.
Toxicology: Non Clinical Safety Data: Chronic toxicity: 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 1,000 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 subcapsular 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 negatives and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture.
Carcinogenicity: A standard battery of laboratory tests did not reveal any genotoxic or mutagenic potential for glimepiride. In a 2 year carcinogenicity study in mice receiving glimepiride in the diet up to 813 mg/kg/day, there was an increase in the incidence of pancreatic islet cell hyperplasia and islet cell adenomas; these are regarded to be the result of chronic stimulation of the pancreatic beta cells. In a 30 months carcinogenicity study in rats receiving glimepiride in the diet up to 345 mg/kg/day, there was an increased incidence of pancreatic islet cell adenomas, however there were considered incidental as there was no dose relationship in either sex. There were no malignant tumours in rats or mice.
Reproduction Toxicity: The sulfonylureas may enter the foetal circulation and cause neonatal hypoglycaemia. In rats, dietary glimepiride at high doses (approx. 82 mg/kg) during gestation caused limb deformations. In rabbits, effects on pregnancy were characterised by increased incidences of abortions/total resorptions and malformations. Similar foetal wastage was not seen in rats although the finding of anophthalmia in a proportion of fetuses may be indicative of a treatment-related effect as eye malformations were found in the rabbit study. Adverse pregnancy outcomes in the rat and rabbit are probably due to the pharmacodynamics effects of glimepiride at excessive doses and are not substance-specific. Glimepiride had no recognizable effects on the rearing, physical development, functional and learning behaviour, memory or fertility of the progeny.
Study in rats showed that glimepiride is excreted in milk. High doses caused hypoglycaemia in suckling young rats. Dietary administration of glimepiride (120-206 mg/kg) during lactation caused limb deformations in adolescent pups from day 4 of lactation onwards.
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