Application of Physiologically-Based Pharmacokinetic Modeling to Understand Drug Disposition in Children with Obesity

Childhood obesity is a significant public health challenge, with ~20% of children in the United States classified as obese today. Data to inform dosing in children with obesity are lacking because there are many ethical and logistical barriers to conducting clinical pharmacokinetic studies. Thus, despite the high prevalence of childhood obesity, few United States Food and Drug Administration labels provide dosing guidance in this population. Physiologically-based pharmacokinetic (PBPK) models can help address this knowledge gap because they can account for physiology and body composition changes to characterize drug exposure in children with obesity with limited data requirements. However, PBPK modeling had not been previously used to predict drug disposition in children with obesity. The overall aim for this dissertation was to develop a systematic approach for applying PBPK modeling to guide the dosing of commonly used drugs in children with obesity. First, in order to use PBPK modeling, a virtual population of children with obesity that included known obesity-induced physiological changes was developed. Key changes relevant to pharmacokinetics in children included increased body size and organ sizes, increased cardiac output and blood flow, and increased glomerular filtration rate. Then, the virtual population was applied to PBPK models of clindamycin, trimethoprim/sulfamethoxazole, fentanyl, methadone, and furosemide, which were developed and/or extended to simulate exposure in children with obesity of various age groups. Children with obesity experienced decreased weight-normalized clearance and volume of distribution. Model simulations support current recommended weight-based dosing for clindamycin and trimethoprim/sulfamethoxazole for children with obesity and highlight potential adjusted dosing with obesity for fentanyl and methadone whilst also considering age and genotype. Finally, this PBPK modeling framework was applied using an extensive electronic health record dataset to explore whether children with obesity receiving enoxaparin experience altered exposure. PBPK model simulations showed that children with obesity have higher anti-Xa concentrations under recommended weight-based dosing than those without obesity owing to reduced weight-normalized clearance, and that both age and obesity status should be considered in enoxaparin dose selection for children. This approach can be applied to study other drugs in children with obesity, for whom there is currently limited dosing guidance.Doctor of Philosoph