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Pharmacology: GLURENORM is a second generation blood sugar lowering sulfonylurea drug. It exhibits pancreatic and extrapancreatic effects.
At the pancreas, gliquidone stimulates the release of insulin from the pancreatic beta cells by potentiation of glucose-mediated insulin release.
In animal studies it seems to reduce the insulin resistance in liver and adipose tissue by increase of insulin receptors and by stimulation of post-receptor mechanism induced by insulin.
The blood glucose lowering effect begins 60 to 90 minutes after oral administration and reaches its maximum 2 to 3 hours after intake of the drug with duration of approximately 8 - 10 hours. Gliquidone can thus be considered as a short acting sulfonylurea and is therefore suitable in Type 2 diabetic patients with increased risk of hypoglycaemia, e.g. the elderly and patients with renal impairment.
Since renal elimination of gliquidone is negligible, GLURENORM may be used in patients with renal impairment or diabetic nephropathy.
In a limited number of diabetic patients eligible for sulfonylurea therapy, who also have concomitant liver diseases, gliquidone has proven to be effective and safe. Only elimination of metabolically inactive metabolites was delayed.
However, severe hepatic impairment represents a contraindication (see Contraindications).
During a clinical study with GLURENORM treatment over a period of 18 and 30 months the mean body weight did not increase but rather decreased by 1 - 2 kg. In a comparative study with several sulfonylureas, patients under GLURENORM therapy had no significant change of body weight after 1 year of treatment.
Pharmacokinetics: Absorption: Following oral administration of single doses of 15 and 30 mg, gliquidone is rapidly and almost completely absorbed (80 - 95%) by the gastro-intestinal tract showing a mean peak plasma concentration of 0.65 μg/mL (range: 0.12 - 2.14 μg/mL). The median time to reach the maximum plasma concentration was 2.25 hours (range: 1.25 - 4.75 hours).
Following a two-compartmental model, the resulting mean area under the concentration-time curve from zero to infinity (AUC0-∞) of gliquidone is 5.1 μg h/mL (range: 1.5 - 10.1 μg h/mL).
No differences in the plasma levels between diabetics and healthy subjects have been reported.
Distribution: Gliquidone is highly bound to plasma proteins (> 99%). There are no clinical data available about the passing of gliquidone or its metabolites across the hematoencephalic barrier or through the placenta. Non-clinical data indicate that gliquidone and its metabolites do not pass across these barriers. No data about the presence of gliquidone in human breast milk are available.
Metabolism: Gliquidone is completely metabolised principally by hydroxylation and demethylation in the liver. The blood metabolites of gliquidone show no or very little pharmacological activity as compared to the parent drug.
Elimination: Gliquidone is mainly excreted as metabolites through the bile with the faeces. Studies with 15 mg of the radiolabeled drug (14C) demonstrated that approximately 86% of the total radioactivity could be recovered in the faeces after oral administration. Independently from the mode of administration and the amount of substance, only a small proportion of the gliquidone dose is excreted via the kidneys and can be found as metabolised drug in the urine (approximately 5%). Even after repeated doses of gliquidone, the renal excretion remains minimal.
Following a two-compartmental model, the mean dominant elimination half-life (t½α) of gliquidone is 1.2 hours (range: 0.4 - 3.0 hours), whereas its mean terminal elimination half-life (t½β) is approximately 8 hours (range: 5.7 - 9.4 hours).
Pharmacokinetics in special population groups: Elderly population: The pharmacokinetics characteristics are essentially equivalent in elderly and middle-aged people.
Renal or hepatic impairment: It has been observed that the metabolism of gliquidone is maintained in patients with hepatic insufficiency. Therefore, gliquidone can be safely used in patients with liver disease. On the other hand, taking into account that most of the drug is excreted via bile in the faeces, no accumulation of the drug in patients with impaired renal function occurs. Consequently, it can be safely administered to patients at risk of chronic nephropathy.
Toxicology: Single- and repeat-dose toxicity studies showed that the toxicity of gliquidone is very low.
Oral LD50 values were > 10 g/kg in mice, rats, rabbits and dogs.
After i.v. administration, LD50 values were 144 - 180 mg/kg in rats.
Oral repeat-dose toxicity studies in rats at dose levels up to 200 mg/kg/day (dietary admixture, 18 months) and 1000 mg/kg/day (gavage, 6 months) did not reveal any relevant adverse effects. Also in dogs, oral administration of up to 20 mg/kg/day for 18 months did not reveal any relevant adverse effects.
In in vitro and in vivo genotoxicity studies (Ames assay, bone marrow micronucleus test in rats, chinese hamsters bone marrow and spermatogonia test), gliquidone did not show any mutagenic or clastogenic effects. Gliquidone was also negative in carcinogenicity studies in mice and rats.
Gliquidone was not teratogenic in rats and rabbits. In rabbits, an increase in the resorption rate was observed at ≥ 50 mg/kg/day attributed to permanent hypoglycaemia in the pregnant females.
