title: Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents.
abstract: OBJECTIVE
  In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.
  
  
  METHODS
  Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.
  
  
  RESULTS
  Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8-55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ).
  
  
  CONCLUSIONS
  The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: van Rongen
authors.affiliation: Division of Anesthesiology and Pain Medicine, Children's National Medical Center, Washington DC, USA.|Division of Clinical Pharmacology, Children's National Medical Center, Washington DC, USA.
authors.forename: Janelle D
authors.initials: JD
authors.lastname: Vaughns
authors.affiliation: Laboratory for Applied PK/PD, Children's Hospital of Philidelphia, Philidelphia, USA.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Moorthy
authors.affiliation: Laboratory for Applied PK/PD, Children's Hospital of Philidelphia, Philidelphia, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.affiliation: Division of Clinical Pharmacology, Children's National Medical Center, Washington DC, USA.|Department of Paediatric Pharmacology, University Children's Hospital, Basel, Switzerland.|Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: van den Anker
mesh_terms: D000293:Adolescent; D001835:Body Weight; D002648:Child; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism*; D050177:Overweight / Q000378:metabolism*; D011446:Prospective Studies
chemical_list: D006993:Hypnotics and Sedatives; D008874:Midazolam
keywords: CYP3A; adolescents; metabolites; midazolam; obesity