Pharmacology: Pharmacodynamics: Mechanism of action: Repaglinide is a short-acting oral secretagogue. Repaglinide lowers the blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning β-cells in the pancreatic islets. Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target protein different from other secretagogues. This depolarises the β-cell and leads to an opening of the calcium channels. The resulting increased calcium influx induces insulin secretion from the β-cell.
Pharmacodynamic effects: In type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after an oral dose of repaglinide. This resulted in a blood glucose-lowering effect throughout the meal period. The elevated insulin levels did not persist beyond the time of the meal challenge. Plasma repaglinide levels decreased rapidly, and low concentrations were seen in the plasma of type 2 diabetic patients 4 hours post-administration.
Clinical efficacy and safety: A dose-dependent decrease in blood glucose was demonstrated in type 2 diabetic patients when administered in doses from 0.5 to 4 mg repaglinide. Clinical study results have shown that repaglinide is optimally dosed in relation to main meals (preprandial dosing). Doses are usually taken within 15 minutes of the meal, but the time may vary from immediately preceding the meal to as long as 30 minutes before the meal.
Pharmacokinetics: Absorption: Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the substance. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%). No clinically relevant differences were seen in the pharmacokinetics of repaglinide, when repaglinide was administered 0, 15 or 30 minutes before a meal or in fasting state. A high interindividual variability (60%) in repaglinide plasma concentrations has been detected in clinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should be titrated against the clinical response, efficacy is not affected by interindividual variability.
Distribution: Repaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent with distribution into intracellular fluid), and is highly bound to plasma proteins in humans (greater than 98%).
Elimination: Repaglinide is eliminated rapidly within 4-6 hours from the blood. The plasma elimination half-life is approximately one hour.
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified. Repaglinide metabolites are excreted primarily via the bile. A small fraction (less than 8%) of the administered dose appears in the urine, primarily as metabolites. Less than 2% of repaglinide is recovered in faeces.
Special patient groups: Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2 diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepatic insufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patients with hepatic insufficiency, and 117.9 ng/ml x hr (83.8) in the elderly type 2 diabetic patients. After a 5 day treatment of repaglinide (2 mg x 3/day) in patients with a severe impaired renal function (creatinine clearance: 20-39 ml/min), the results showed a significant 2-fold increase of the exposure (AUC) and half-life (t½) as compared to patients with normal renal function.
Paediatric population: No data available.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Repaglinide was not teratogenic in animal studies. Embryotoxicity, abnormal limb development in rat foetuses and newborn pups, was observed in female rats exposed to high doses in the last stage of pregnancy and during the lactation period. Repaglinide was detected in the milk of animals.