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

Abstract

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.

Drug dosing in children with obesity: a narrative updated review

“…Given the relentless rise incidence in childhood obesity, the problem faced by clinicians is considerably even more complicated. Physiology, drug parameters, patient factors, and methodology need to be accounted for while studying the influence of obesity on pharmacokinetics in children [76]. Despite signs of progress in knowledge on pharmacodynamics, pharmacokinetics, and other aspects of pharmacology, one is generally prone to determine drug dosing bearing in mind only the weight of the child.…”

Perioperative Acetaminophen Dosing in Obese Children

“…These models have the capacity for incorporation of so much more information, such as pharmacogenomics or environmental influences [ 31 , 32 ]. Physiological models are capable of using existing information about obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathways) [ 33 ]. This type of modelling has been used successfully to investigate clindamycin, trimethoprim/sulfamethoxazole, and metformin to better understand the dosing of these drugs in children with obesity [ 34 , 35 ].…”

Melatonin Prescription in Children and Adolescents in Relation to Body Weight and Age

“…Increased liver size, hepatic perfusion and glomerular filtration rate have been reported in children with obesity. The rate-limiting pharmacokinetic and physiological variables do not display alterations that are proportionate with the increase in body size [ 19 ]. Therefore, the conventional mg/kg dosing may not be applicable in children with obesity.…”

“…Therefore, the conventional mg/kg dosing may not be applicable in children with obesity. Pediatric pharmacokinetic studies rarely include data for the population of children with obesity and hence, this is an area where knowledge gaps are especially large [ 19 ]. For melatonin, the starting dose according to the information in the summary of product characteristics for melatonin products approved by the European Medicines Agency (EMA), as well as recommendations in Nordic national guidelines [ 9 , 10 ], is 1–5 mg in children 4 years of age and older.…”