Use of physiologically‐based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity

Abstract

Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically‐based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity‐induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady‐state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically‐based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.

Predicting the correct dose in children: Role of computational Pediatric Physiological‐based pharmacokinetics modeling tools

“…COVID-19, coronavirus disease 2019; P-PBPK, pediatric physiologically-based pharmacokinetic the area of people preferred to use PK-Sim; however, this does not necessarily mean that the software was only used for the obesity area of applications, but because obesity research is completed by the same team. [57][58][59][60] These findings can be used to improve the design of the current P-PBPK model and highlight the need for childhood obesity dosing research. The COVID-19 infection in children has attracted attention from experts in pharmaceutics since 2020 (Figure 4).…”

“…Authors have developed multiple PBPK models using PK‐Sim (version 9.0) for children with obesity with different drugs or diseases. In one study, PBPK models were developed and scaled to children with obesity to evaluate the interplay of obesity, age, and genetic variation in the exposure to fentanyl and methadone and to avoid serious adverse events associated with overexposure 58 . Another study provides a deeper understanding of the influence of age and obesity on metformin PK and offers guidance on dosing 59 .…”

“…Verified PBPK models of drugs are presented in support of pediatric dose prediction (Figure 4 ): 13 articles reported results from P‐PBPK models, which are presented in support of dose selection, 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 five articles were on the optimization of dosage in the design of future pediatric clinical studies, 3 , 29 , 43 , 44 , 45 and six articles reported findings from studies on determining dose regimens. 46 , 47 , 48 , 49 , 50 , 51 Fourteen publications were on some special pediatric populations and uncommon diseases with an assessment of renal impairment, 52 , 53 , 54 , 55 , 56 children with obesity, 57 , 58 , 59 , 60 and pediatric patients with severe coronavirus disease 2019 (COVID‐19) disease. 61 , 62 , 63 , 64 , 65 Consistent with this trend, several big research funding/grants for computational pharmaceutics worldwide were launched (Table 1 ).…”

“…69 P‐PBPK modeling can bridge the gap in understanding obesity‐related physiological changes in children. In 2022, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) funds a series of studies that address dosing guidance for children with obesity, 57 , 58 , 59 , 60 which Jacqueline G. Gerhart's group conducted. Authors have developed multiple PBPK models using PK‐Sim (version 9.0) for children with obesity with different drugs or diseases.…”

“…However, this does not mean that one of the software tools must be used for particular areas (e.g., the amount of Simcyp and PK‐Sim were almost equal in the dose selection; Figure 5). For the area of obesity, people preferred to use PK‐Sim; however, this does not necessarily mean that the software was only used for the obesity area of applications, but because obesity research is completed by the same team 57–60 . These findings can be used to improve the design of the current P‐PBPK model and highlight the need for childhood obesity dosing research.…”