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Drug Dosing and Pharmacokinetics in Children With Obesity A Systematic Review

Margreet W. Harskamp-van Ginkel, MD1,2,3; Kevin D. Hill, MD1,2; Kristian C. Becker, BA1,2; Daniela Testoni, MD, MHS1,2; Michael Cohen-Wolkowiez, MD, PhD1,2; Daniel Gonzalez, PharmD, PhD1,2,4; Jeffrey S. Barrett, PhD5; Daniel K. Benjamin Jr, MD, PhD, MPH1,2; David A. Siegel, MD6; Patricia Banks, BS1,2; Kevin M. Watt, MD1,2 ; for the Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee
[+] Author Affiliations
1Department of Pediatrics, Duke University, Durham, North Carolina
2Duke Clinical Research Institute, Duke University, Durham, North Carolina
3Academic Medical Center, Department of Public Health, Amsterdam, the Netherlands
4Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill
5Department of Clinical Pharmacology and Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
6Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
JAMA Pediatr. 2015;169(7):678-685. doi:10.1001/jamapediatrics.2015.132.
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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.

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Figure 1.
PRISMA Diagram of Study Selection

Study outline of the systematic literature search and inclusion of identified articles.

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Figure 2.
Relationship Between Obesity-Related Changes in Pharmacokinetics and Drug Physicochemical Properties

Volume of distribution and clearance ratios plotted by measured lipophilicity (logP) and Biopharmaceutical Drug Disposition Classification System (BDDCS) class. Clearance and volume of distribution are weight-normalized (eg, volume of distribution in L/kg). If authors did not report weight-normalized values (eg, for antipyrine, carbamazepine, and caffeine), then weight-normalized parameters were calculated by dividing reported values by individual or study mean weight values. A, Volume of distribution by measured logP; B, Volume of distribution by BDDCS class; C, Clearance by measured logP; D, Clearance by BDDCS class. ace indicates acetaminophen; ant, antipyrine; caf, caffeine; cbz, carbamazepine; dox, doxorubicin; eto, etoposide; gen, gentamicin; mer, mercaptopurine; mtx, methotrexate; ten, teniposide; the, theophylline; and van, vancomycin.

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