Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AMMTeK, 8 rue Campagne Première, 75014 Paris, France, Tel: +33 (0)6 74 29 38 14
Pharmacotherapeutic group: Drugs used in diabetes, sulphonylureas
ATC code: A10BB01
Sulphonylureas act on pancreatic beta-cells by inhibiting ATP-sensitive potassium channels. The mechanisms of action proposed for this effect include stimulation of insulin release by beta-cells of the pancreas.
The minimum active concentration for the effect is considered to be 30-50 ng/mL glibenclamide.
Glibenclamide, a second-generation, short half-life sulphonylurea, is a hypoglycaemic agent that reduces blood-glucose by stimulating insulin release by the pancreas; this effect depends on the presence of active beta-cells or beta-cells made active by glibenclamide in the pancreatic islets in certain cases of neonatal diabetes.
Stimulation of insulin secretion by glibenclamide in response to a meal is of major significance. Administering glibenclamide to a diabetic enhances the post-prandial insulinotropic response. Post-prandial responses involving secretion of insulin and peptide-C continue to be enhanced after at least 6 months of treatment and even over many years in the case of neonatal diabetes by potassium channel disorders.
Glibenclamide has been shown to be effective in patients with mutations in the genes coding for the β-cell ATP-sensitive potassium channel and chromosome 6q24-related transient neonatal diabetes mellitus.
Treatment using sulphonylureas in neonatal diabetes linked to potassium channel disorders is supported by published studies showing measurable improvements in glycaemic control and suggesting neuro-psychomotor and neuro-psychological deficiencies, which are greater in younger patients.
From data published in the literature, treatment with sulfonylurea is reported to be successful in approximately 90% of the patients with neonatal diabetes associated with K-ATP channel mutations. The average dose reported in the literature (clinical trials and case reports) is of approximately 0.5 mg/kg/day. When limited to clinical trials or prospective data collections only, the average dose decreases to 0.2 to 0.3 mg/kg/day. Higher doses have occasionally been reported in the literature with doses as high as 2.8 mg/kg/day without undesirable effects and with full transfer off insulin.
In a phase II, single-centre, prospective, open-label, non-randomised study, acceptability, efficiency and tolerance of the switch from crushed tablets to glibenclamide suspension were measured. Ten patients (7 boys/3 girls) with KCNJ11 mutation, with median age 2.7 years (0.3 to 16.2) andmedian duration of glibenclamide therapy 2.3 years (6 days to 11.3 years) were treated. Daily doses ranged from 0.1 to 0.8 mg/kg for glibenclamide tablets (median dose, 0.3 mg/kg) and from 0.1 to 0.6 mg/kg for oral suspension (median 0.1 to 0.2 mg/kg/day over the study period) given in 2 to 4 administration per day.
After switching from glibenclamide tablets to glibenclamide suspension, there was no significant change in glycaemic control as evidenced from the similar serum HbA1c (6.5 vs 6.1% at Visits M0 and M4, respectively; p=0.076) and fructosamine (283.4 vs 271.2 µmol/L at Visits M0 and M4, respectively; p=0.55) mean concentrations.
None of patients experienced deterioration in glycaemic control, defined as an increase of HbA1c by >0.5% and exceeding 5.6% in patients with baseline HbA1c ≤5.6% or an increase of HbA1c by >0.5% in patients with baseline HbA1c >5.6%.
A large international long-term term study of treatment for neonatal diabetes due to KCNJ11 mutations is ongoing and results were reported in 81 patients of the 90 patients originally included with a median [interquartile range] follow-up duration of 10.2 years [9.3-10.8 years]. Transfer to sulfonylureas occurred in childhood with a median [IQR] at transfer of 4.8 years [1.7–11.4 years]. Seventy-five patients (93%) remained on sulphonylurea alone at most recent follow-up and 6/81(7%) were on sulphonylurea and daily insulin. In patients on sulphonylurea alone, blood glucose control has been improved after transfer to sulfonylureas with median [IQR] HbA1c of 5.9% [5.4-6.5%] at 1 year vs 8.0 % [7.2-9.2%] before transfer (p<0.0001), and remained very well controlled after 10 years with a median [IQR] HbA1c of 6.4% [5.9-7.2%].
The median [IQR] dose of sulfonylurea fell over the follow-up with a median [IQR] dose of 0.30 mg/kg/day [0.14-0.53] mg/kg/day at one year and of 0.23 mg/kg/day [0.12-0.41 mg/kg/day] at 10 years, p=0.03). There were no reported episodes of severe hypoglycaemia. Adverse reactions (diarrhoea/nausea/reduced appetite/abdominal pain) were reported in 10/81(12%); these were transient, and no patients discontinued sulphonylurea as a result. Microvascular complications were reported in 7/81(9%) patients; there were no macrovascular complications. Patients with complications were older at age of transfer to sulfonylurea than those without complications (median age at transfer: 20.5 v 4.1 years, p=0.0005). Oral glucose tolerance tests and intravenous glucose tolerance tests revealed good insulin response to glucose and maintained incretin effect after ten years.
Evidence exists that administration of glibenclamide might improve some neurological deficits in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations like epilepsy, motor function and hypotonia, by a mechanism independent from insulin secretion.
Earlier treatment initiation might be associated with greater benefits.
After oral administration, glibenclamide is absorbed rapidly and induces its effect within 2.5 hours with a duration of up to 15 hours, although the elimination half-life is 5 to 10 hours. The food effect on the speed or the level of absorption of glibenclamide oral suspension has not been investigated.
Bioavailability studies have demonstrated that nonmicronised tablets provide serum glibenclamide concentrations that are not bioequivalent to those from micronised tablets.
Head to head comparative pharmacokinetic data following the application of glibenclamide suspension and micronised tablets are not available. The conversion rate between micronised tablets and the suspension has not been established.
A comparative study of relative bioavailability between two suspensions of glibenclamide oral suspensions (0.6 mg/mL and 6 mg/mL) and crushed glibenclamide tablets (Daonil 5 mg) showed that when glibenclamide oral suspensions were administered, peak plasma concentrations of glibenclamide are reached 0.5 hours earlier than that observed with the crushed Daonil tablet (median value after administration is 2.5 hours compared to 3 hours). The values for maximum plasma concentrations (Cmax) were similar for the two suspensions (201.71 ± 71.43 ng/mL for the 6 mg/mL suspension and 206.93 ± 67.33 ng/mL for the 0.6 mg/mL suspension). These values were approx. 40% greater than those obtained for the crushed tablet (148.34 ± 46.74 ng/mL).
The exposures were respectively similar for the two glibenclamide oral suspensions, and greater than those observed after administration of crushed Daonil tablets. The relative bioavailability was 121.6% for the 0.6 mg/mL suspension and 114.1% for the 6 mg/mL suspension compared to the crushed Daonil tablets.
Population pharmacokinetic approach was used to compare steady state concentrations following 0.9 mg twice daily in children with body weights between 10–30 kg and 1.25 mg twice daily in adults. The plasma glibenclamide levels in the simulated paediatric population were approximately 30%-60% lower than the adult levels. With smaller bodyweight the concentration increased but exceeded the adult plasma levels in minimal extents only for poor metabolizers. Distribution
Glibenclamide is strongly bound to plasma albumin (99%), which may account for certain drug interactions, but is not easily detached by acidic medicinal products.
Glibenclamide is completely metabolised by the liver into 3 inactive metabolites excreted via bile (60%) and urine (40%); elimination is complete in 45 to 72 hours. Clinical studies appear to suggest that CYP2C9 contributes significantly to glibenclamide metabolism in vivo.
Liver failure reduces the metabolism of glibenclamide and therefore significantly slows down its elimination.
Biliary excretion of the metabolites increases in the event of kidney failure, proportionally to the severity of the change in renal function. Kidney failure does not affect its elimination as long as creatinine clearance remains above 30 ml/min.
The elimination half-lives were similar for the two suspensions (almost 8 hours) and a little shorter than those observed with the crushed Daonil tablets.
In repeated dose toxicity studies with oral administration of high doses of glibenclamide, effects on pancreatic beta-cells were observed (enlargement of the islets of Langerhans with irregularly configured islets and reduction in pancreatic β-cell granulation in rats at doses of ≥30 mg/kg/day, beta-cell exhaustion as indicated by depletion of insulin-containing granules in rabbits at doses of ≥100 mg/kg/day).
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