title: Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review.
abstract: OBJECTIVE
  Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown.
  
  
  OBJECTIVE
  To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children.
  
  
  METHODS
  We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution.
  
  
  RESULTS
  Twenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity.
  
  
  CONCLUSIONS
  Consensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina3Academic Medical Center, Department of Public Health, Amsterdam, the Netherlands.
authors.forename: Margreet W
authors.initials: MW
authors.lastname: Harskamp-van Ginkel
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hill
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Kristian C
authors.initials: KC
authors.lastname: Becker
authors.forename: Kristian
authors.initials: K
authors.lastname: Becker
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Testoni
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina4Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Siegel
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Patricia
authors.initials: P
authors.lastname: Banks
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Watt
mesh_terms: D001823:Body Composition; D001835:Body Weight / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D054796:Drug Dosage Calculations; D006801:Humans; D008657:Metabolic Clearance Rate / Q000502:physiology*; D009765:Obesity / Q000188:drug therapy*; D010599:Pharmacokinetics