Drug dosing and pharmacokinetics in children with obesity a systematic review

Margreet W. Harskamp-Van Ginkel; Kevin D. Hill; Kristian Becker; Daniela Testoni; Michael Cohen-Wolkowiez; Daniel Gonzalez; Jeffrey S. Barrett; Daniel K. Benjamin; David A. Siegel; Patricia Banks; Kevin M. Watt; Katherine Y. Berezny; Edmund Capparelli; Gregory L. Kearns; Matthew Laughon; Andre Muelenaer; T. Michael O'Shea; Ian M. Paul; John Van Den Anker; Kelly Wade; Thomas J. Walsh

doi:10.1001/jamapediatrics.2015.132

Drug dosing and pharmacokinetics in children with obesity a systematic review

Margreet W. Harskamp-Van Ginkel, Kevin D. Hill, Kristian Becker, Daniela Testoni, Michael Cohen-Wolkowiez, Daniel Gonzalez, Jeffrey S. Barrett, Daniel K. Benjamin, David A. Siegel, Patricia Banks, Kevin M. Watt, Katherine Y. Berezny, Edmund Capparelli, Gregory L. Kearns, Matthew Laughon, Andre Muelenaer, T. Michael O'Shea, Ian M. Paul, John Van Den Anker, Kelly WadeThomas J. Walsh

Research output: Contribution to journal › Review article › peer-review

77 Scopus citations

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 studiesmet 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.

Original language	English (US)
Pages (from-to)	678-685
Number of pages	8
Journal	JAMA Pediatrics
Volume	169
Issue number	7
DOIs	https://doi.org/10.1001/jamapediatrics.2015.132
State	Published - Jul 1 2015

All Science Journal Classification (ASJC) codes

Pediatrics, Perinatology, and Child Health

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10.1001/jamapediatrics.2015.132

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Harskamp-Van Ginkel, M. W., Hill, K. D., Becker, K., Testoni, D., Cohen-Wolkowiez, M., Gonzalez, D., Barrett, J. S., Benjamin, D. K., Siegel, D. A., Banks, P., Watt, K. M., Berezny, K. Y., Capparelli, E., Kearns, G. L., Laughon, M., Muelenaer, A., O'Shea, T. M., Paul, I. M., Van Den Anker, J., ... Walsh, T. J. (2015). Drug dosing and pharmacokinetics in children with obesity a systematic review. JAMA Pediatrics, 169(7), 678-685. https://doi.org/10.1001/jamapediatrics.2015.132

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title = "Drug dosing and pharmacokinetics in children with obesity a systematic review",

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 studiesmet 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.",

author = "{Harskamp-Van Ginkel}, {Margreet W.} and Hill, {Kevin D.} and Kristian Becker and Daniela Testoni and Michael Cohen-Wolkowiez and Daniel Gonzalez and Barrett, {Jeffrey S.} and Benjamin, {Daniel K.} and Siegel, {David A.} and Patricia Banks and Watt, {Kevin M.} and Berezny, {Katherine Y.} and Edmund Capparelli and Kearns, {Gregory L.} and Matthew Laughon and Andre Muelenaer and O'Shea, {T. Michael} and Paul, {Ian M.} and {Van Den Anker}, John and Kelly Wade and Walsh, {Thomas J.}",

year = "2015",

month = jul,

day = "1",

doi = "10.1001/jamapediatrics.2015.132",

language = "English (US)",

volume = "169",

pages = "678--685",

journal = "JAMA Pediatrics",

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Harskamp-Van Ginkel, MW, Hill, KD, Becker, K, Testoni, D, Cohen-Wolkowiez, M, Gonzalez, D, Barrett, JS, Benjamin, DK, Siegel, DA, Banks, P, Watt, KM, Berezny, KY, Capparelli, E, Kearns, GL, Laughon, M, Muelenaer, A, O'Shea, TM, Paul, IM, Van Den Anker, J, Wade, K & Walsh, TJ 2015, 'Drug dosing and pharmacokinetics in children with obesity a systematic review', JAMA Pediatrics, vol. 169, no. 7, pp. 678-685. https://doi.org/10.1001/jamapediatrics.2015.132

TY - JOUR

T1 - Drug dosing and pharmacokinetics in children with obesity a systematic review

AU - Harskamp-Van Ginkel, Margreet W.

AU - Hill, Kevin D.

AU - Becker, Kristian

AU - Testoni, Daniela

AU - Cohen-Wolkowiez, Michael

AU - Gonzalez, Daniel

AU - Barrett, Jeffrey S.

AU - Benjamin, Daniel K.

AU - Siegel, David A.

AU - Banks, Patricia

AU - Watt, Kevin M.

AU - Berezny, Katherine Y.

AU - Capparelli, Edmund

AU - Kearns, Gregory L.

AU - Laughon, Matthew

AU - Muelenaer, Andre

AU - O'Shea, T. Michael

AU - Paul, Ian M.

AU - Van Den Anker, John

AU - Wade, Kelly

AU - Walsh, Thomas J.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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 studiesmet 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.

AB - 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 studiesmet 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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U2 - 10.1001/jamapediatrics.2015.132

DO - 10.1001/jamapediatrics.2015.132

M3 - Review article

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SN - 2168-6203

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EP - 685

JO - JAMA Pediatrics

JF - JAMA Pediatrics

IS - 7

ER -

Drug dosing and pharmacokinetics in children with obesity a systematic review

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