Margreet W Harskamp-van Ginkel1, Kevin D Hill2, Kristian C Becker2, Kristian Becker, Daniela Testoni2, Michael Cohen-Wolkowiez2, Daniel Gonzalez3, Jeffrey S Barrett4, Daniel K Benjamin2, David A Siegel5, Patricia Banks2, Kevin M Watt2. 1. 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. 2. Department of Pediatrics, Duke University, Durham, North Carolina2Duke Clinical Research Institute, Duke University, Durham, North Carolina. 3. 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. 4. Department of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 5. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
Abstract
IMPORTANCE: 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. EVIDENCE REVIEW: 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. FINDINGS: 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 AND RELEVANCE: 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.
IMPORTANCE: 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. EVIDENCE REVIEW: 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. FINDINGS: 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 AND RELEVANCE: 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: Carolyn L Westhoff; Anupama H Torgal; Elizabeth R Mayeda; Malcolm C Pike; Frank Z Stanczyk Journal: Contraception Date: 2010-02-20 Impact factor: 3.375
Authors: Nobuko Hijiya; John C Panetta; Yinmei Zhou; Emily P Kyzer; Scott C Howard; Sima Jeha; Bassem I Razzouk; Raul C Ribeiro; Jeffrey E Rubnitz; Melissa M Hudson; John T Sandlund; Ching-Hon Pui; Mary V Relling Journal: Blood Date: 2006-08-17 Impact factor: 22.113
Authors: Sin Yin Lim; Sukyung Woo; Jamie L Miller; Teresa V Lewis; Emilie D Henry; Peter N Johnson Journal: J Pediatr Pharmacol Ther Date: 2018 May-Jun
Authors: Takuto Takahashi; Angela R Smith; Pamala A Jacobson; James Fisher; Nathan T Rubin; Mark N Kirstein Journal: Antimicrob Agents Chemother Date: 2020-11-17 Impact factor: 5.191