Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling

Abstract

Background and Objective While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. Methods To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. Results Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. Conclusions Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.The members of "on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee" is present in the Acknowledgements section.

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

“…V ss can be defined using the equation below: where V plasma is plasma volume, V tissue is tissue water volume, f u,p is fraction unbound in plasma, and f u,t is fraction unbound in tissue. Increased V plasma and V tissue (given more distribution space) can increase cardiac output during obesity ( Vasan, 2003 ; Colles et al, 2006 ; Gerhart et al, 2021 ), potentially increasing the V ss on an absolute scale. However, the extent of increase in V ss is also dependent on the drug binding to plasma protein (that determines ) as well as to the tissue components (that determines ), which are potentially altered due to altered composition during obesity.…”

“…However, the extent of increase in V ss is also dependent on the drug binding to plasma protein (that determines ) as well as to the tissue components (that determines ), which are potentially altered due to altered composition during obesity. While studies have shown that plasma composition with respect to serum albumin and hematocrit are largely unaffected by obesity, it changes with respect to α 1-acid glycoprotein (AAG), which increases approximately 2-fold with obesity in adults ( Benedek et al, 1983 , 1984 ; Blouin et al, 1987 ; Gerhart et al, 2021 ). However, this increase in AAG has not yet been identified in pediatric populations with obesity due to limited studies ( Gerhart et al, 2021 ).…”

“…While studies have shown that plasma composition with respect to serum albumin and hematocrit are largely unaffected by obesity, it changes with respect to α 1-acid glycoprotein (AAG), which increases approximately 2-fold with obesity in adults ( Benedek et al, 1983 , 1984 ; Blouin et al, 1987 ; Gerhart et al, 2021 ). However, this increase in AAG has not yet been identified in pediatric populations with obesity due to limited studies ( Gerhart et al, 2021 ).…”

“…An increase in body fat with obesity is also accompanied by an increase in lean mass to provide additional structural (e.g., increased skeletal strength) and functional (e.g., increased metabolic need) support due to extra weight gain from adiposity. For example, key clearance organs such as the kidney and liver increase 19% and 18% in mass on average, respectively, with obesity ( Nawaratne et al, 1998 ; Gerhart et al, 2021 ). These organ mass increases were determined by a series of magnetic resonance imaging and dual x-ray absorptiometry studies in adults and ultrasound scans in pediatric populations with and without obesity ( Hwaung et al, 2019 ; Gerhart et al, 2021 ).…”

“…For example, key clearance organs such as the kidney and liver increase 19% and 18% in mass on average, respectively, with obesity ( Nawaratne et al, 1998 ; Gerhart et al, 2021 ). These organ mass increases were determined by a series of magnetic resonance imaging and dual x-ray absorptiometry studies in adults and ultrasound scans in pediatric populations with and without obesity ( Hwaung et al, 2019 ; Gerhart et al, 2021 ). Unlike body fat, these increases in non-fat organs do not increase proportionately with obesity.…”