Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia

Eur J Clin Pharmacol. 2016 Nov;72(11):1373-1379. doi: 10.1007/s00228-016-2119-9. Epub 2016 Aug 25.


Purpose: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy.

Methods: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients). A total of 229 plasma Gb concentrations and 187 blood glucose measurements were available. A population model was developed with NONMEM.

Results: Body weight was the most significant parameter on clearance and explained a substantial part of the variability. A variant genotype of CYP2C9 (i.e., *1/*2 and *1/*3) explained also a part of the remaining variability on Gb clearance. Patients carrying these allelic variants had a clearance decreased by 45 %. A link between daily area under the curve (AUC0-24 h) and metabolic control diabetes was found.

Conclusions: This study evaluates for the first time the pharmacokinetics of oral Gb in children and constitutes a first step towards dose individualization of this drug in a particularly vulnerable population.

Keywords: Children; Diabetes mellitus; Glibenclamide; Neonatal diabetes mellitus; Neonatal syndromic hyperglycemia; Population pharmacokinetics.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Administration, Oral
  • Blood Glucose / analysis
  • Child
  • Child, Preschool
  • Cytochrome P-450 CYP2C9 / genetics
  • Dose-Response Relationship, Drug
  • Genotype
  • Glyburide / administration & dosage
  • Glyburide / blood
  • Glyburide / pharmacokinetics*
  • Glyburide / therapeutic use
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / drug therapy
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / therapeutic use
  • Injections, Subcutaneous
  • Insulin / administration & dosage
  • Insulin / therapeutic use
  • Models, Biological*
  • Mutation
  • Off-Label Use
  • Potassium Channels, Inwardly Rectifying / genetics
  • Sulfonylurea Receptors / genetics
  • Syndrome
  • Tablets


  • ABCC8 protein, human
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Sulfonylurea Receptors
  • Tablets
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Glyburide