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Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations

Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure...

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Autores principales: Gerhart, Jacqueline G., Balevic, Stephen, Sinha, Jaydeep, Perrin, Eliana M., Wang, Jian, Edginton, Andrea N., Gonzalez, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960278/
https://www.ncbi.nlm.nih.gov/pubmed/35359853
http://dx.doi.org/10.3389/fphar.2022.818726
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author Gerhart, Jacqueline G.
Balevic, Stephen
Sinha, Jaydeep
Perrin, Eliana M.
Wang, Jian
Edginton, Andrea N.
Gonzalez, Daniel
author_facet Gerhart, Jacqueline G.
Balevic, Stephen
Sinha, Jaydeep
Perrin, Eliana M.
Wang, Jian
Edginton, Andrea N.
Gonzalez, Daniel
author_sort Gerhart, Jacqueline G.
collection PubMed
description Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure (and thus dosing), can vary significantly between patients with and without obesity. Obesity-related physiological changes, such as increased tissue volume and perfusion, altered blood protein concentrations, and tissue composition can greatly affect a drug’s volume of distribution, which might necessitate adjustment in loading doses. Obesity-related changes in the drug eliminating organs, such as altered enzyme activity in the liver and glomerular filtration rate, can affect the rate of drug elimination, which may warrant an adjustment in the maintenance dosing rate. Although weight-based dosing (i.e., in mg/kg) is commonly practiced in pediatrics, choice of the right body size metric (e.g., total body weight, lean body weight, body surface area, etc.) for dosing children with obesity still remains a question. To address this gap, the interplay between obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathway) needs to be characterized in a quantitative framework. Additionally, methodological considerations, such as adequate sample size and optimal sampling scheme, should also be considered to ensure accurate and precise top-down covariate selection, particularly when designing opportunistic studies in pediatric drug development. Further factors affecting dosing, including existing dosing recommendations, target therapeutic ranges, dose capping, and formulations constraints, are also important to consider when undergoing dose selection for children with obesity. Opportunities to bridge the dosing knowledge gap in children with obesity include modeling and simulating techniques (i.e., population pharmacokinetic and physiologically-based pharmacokinetic [PBPK] modeling), opportunistic clinical data, and real world data. In this review, key considerations related to physiology, drug parameters, patient factors, and methodology that need to be accounted for while studying the influence of obesity on pharmacokinetics in children are highlighted and discussed. Future studies will need to leverage these modeling opportunities to better describe drug exposure in children with obesity as the childhood obesity epidemic continues.
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spelling pubmed-89602782022-03-30 Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations Gerhart, Jacqueline G. Balevic, Stephen Sinha, Jaydeep Perrin, Eliana M. Wang, Jian Edginton, Andrea N. Gonzalez, Daniel Front Pharmacol Pharmacology Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure (and thus dosing), can vary significantly between patients with and without obesity. Obesity-related physiological changes, such as increased tissue volume and perfusion, altered blood protein concentrations, and tissue composition can greatly affect a drug’s volume of distribution, which might necessitate adjustment in loading doses. Obesity-related changes in the drug eliminating organs, such as altered enzyme activity in the liver and glomerular filtration rate, can affect the rate of drug elimination, which may warrant an adjustment in the maintenance dosing rate. Although weight-based dosing (i.e., in mg/kg) is commonly practiced in pediatrics, choice of the right body size metric (e.g., total body weight, lean body weight, body surface area, etc.) for dosing children with obesity still remains a question. To address this gap, the interplay between obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathway) needs to be characterized in a quantitative framework. Additionally, methodological considerations, such as adequate sample size and optimal sampling scheme, should also be considered to ensure accurate and precise top-down covariate selection, particularly when designing opportunistic studies in pediatric drug development. Further factors affecting dosing, including existing dosing recommendations, target therapeutic ranges, dose capping, and formulations constraints, are also important to consider when undergoing dose selection for children with obesity. Opportunities to bridge the dosing knowledge gap in children with obesity include modeling and simulating techniques (i.e., population pharmacokinetic and physiologically-based pharmacokinetic [PBPK] modeling), opportunistic clinical data, and real world data. In this review, key considerations related to physiology, drug parameters, patient factors, and methodology that need to be accounted for while studying the influence of obesity on pharmacokinetics in children are highlighted and discussed. Future studies will need to leverage these modeling opportunities to better describe drug exposure in children with obesity as the childhood obesity epidemic continues. Frontiers Media S.A. 2022-03-10 /pmc/articles/PMC8960278/ /pubmed/35359853 http://dx.doi.org/10.3389/fphar.2022.818726 Text en Copyright © 2022 Gerhart, Balevic, Sinha, Perrin, Wang, Edginton and Gonzalez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Gerhart, Jacqueline G.
Balevic, Stephen
Sinha, Jaydeep
Perrin, Eliana M.
Wang, Jian
Edginton, Andrea N.
Gonzalez, Daniel
Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title_full Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title_fullStr Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title_full_unstemmed Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title_short Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
title_sort characterizing pharmacokinetics in children with obesity—physiological, drug, patient, and methodological considerations
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960278/
https://www.ncbi.nlm.nih.gov/pubmed/35359853
http://dx.doi.org/10.3389/fphar.2022.818726
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