title: Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia.
abstract: OBJECTIVE
  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.
authors: EA 7323, Université Paris Descartes Sorbonne Paris Cité, Paris, France. naim.bouazza@cch.aphp.fr.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, 89 rue d'Assas, 75006, Paris, France. naim.bouazza@cch.aphp.fr.|CIC-0901 Inserm, Cochin-Necker, Paris, France. naim.bouazza@cch.aphp.fr.
authors: Naïm
authors: N
authors: Bouazza
authors: Laboratoire de Pharmacologie-Toxicologie, Hôpital Maison Blanche, Centre Hospitalier et Universitaire de Reims, Reims, France.
authors: Zoubir
authors: Z
authors: Djerada
authors: Laboratoire de Pharmacologie-Toxicologie, Hôpital Maison Blanche, Centre Hospitalier et Universitaire de Reims, Reims, France.
authors: Claire
authors: C
authors: Gozalo
authors: Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Kanetee
authors: K
authors: Busiah
authors: Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|Université Paris Descartes Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors: Jacques
authors: J
authors: Beltrand
authors: Université Paris Descartes Sorbonne Paris Cité, Institut IMAGINE, Paris, France.|Inserm U1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
authors: Marianne
authors: M
authors: Berdugo
authors: EA 7323, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, 89 rue d'Assas, 75006, Paris, France.|CIC-0901 Inserm, Cochin-Necker, Paris, France.
authors: Saik
authors: S
authors: Urien
authors: EA 7323, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, 89 rue d'Assas, 75006, Paris, France.|CIC-0901 Inserm, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors: Jean-Marc
authors: JM
authors: Treluyer
authors: Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|Inserm U1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
authors: Michel
authors: M
authors: Polak
mesh_terms: D000284:Administration, Oral; D001786:Blood Glucose / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D005905:Glyburide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008954:Models, Biological; D009154:Mutation; D056687:Off-Label Use; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D064233:Sulfonylurea Receptors / Q000235:genetics; D013577:Syndrome; D013607:Tablets; D000099161:Kcnj11 Channel
chemical_list: D001786:Blood Glucose; D065729:Cytochrome P-450 CYP2C9; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D013607:Tablets; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C450260:CYP2C9 protein, human
keywords: Children; Diabetes mellitus; Glibenclamide; Neonatal diabetes mellitus; Neonatal syndromic hyperglycemia; Population pharmacokinetics