1. Introduction

Despite the progressive increase in obesity and its associated chronic diseases in children, there is limited evidence on the optimal dosage of most medications for obese children and adolescents. This review analyzes the influence of pathophysiological changes on pharmacokinetics and pharmacodynamics and also explores the body size descriptors used in clinical practice.

Patients with obesity present significant pathophysiological alterations, such as a significant increase in the fat/lean mass ratio, increased blood flow and cardiac output, and changes in plasma protein binding, which may affect the volume of distribution of drugs and the adjustment of the loading dose. In these patients, there appears to be a slight increase in the distribution volume of hydrophilic drugs, while it varies significantly—depending on the drug and other factors such as affinity to other tissues—for lipophilic drugs.

On the other hand, reduction in tissue perfusion, alteration of liver enzyme activity, and an increase in liver and kidney mass and blood flow have been reported, leading to a possible alteration in drug clearance and possible adjustments to maintenance regimens.

Furthermore, there are many body size descriptors that have been described for scaling doses in pediatrics, and they can sometimes differ for calculating the loading dose and the maintenance dose. Regardless of the descriptor used, the maximum dose (capping) must always be considered. If this is not established in pediatrics, we should not exceed the doses recommended for adult patients and, in certain cases, those for obese adults. It is difficult to establish a single dosing strategy for the obese population given the lack of studies confirming the extent of changes in pharmacokinetic processes, which will also depend on the properties of each drug, such as liposolubility and elimination pathways.

This review highlights that the impact of excess body mass in pediatric patients on drug clearance and distribution volume remains insufficiently characterized.

Due to the continuing increase in the prevalence of childhood obesity, a better understanding of how obesity affects PK/PD is a priority in order to optimize dosing regimens for patients with excess body weight.

To improve the safety and efficacy of drug treatments for the pediatric population with excess body weight, clinical studies should include more representative pediatric cohorts covering a wide range of body sizes and always taking into account the ethical issues arising from the inclusion of obese children in clinical trials. Another strategy would be to develop prospective randomized studies with different dosage forms in order to determine the optimal size descriptor for obese and/or overweight children.

On the other hand, modeling and simulation tools are presented as an alternative for understanding PK variables in obese children, in addition to promoting the collection of clinical data and fostering close collaboration between healthcare professionals and research institutions.

The two models frequently used are those based on population pharmacokinetic data (PopPK) and those that take into account the characteristics of the drug and physiological changes in obese patients (PBPK models).

2. PopPK and PBPK Models

PopPK analysis is a useful tool for predicting individualized PK parameters (such as AUC, minimum steady-state concentration, Vd, and Cl) using Bayesian estimation based on a specific population model. The advantage of this analysis is that few blood samples are needed for dose adjustment; however, on the other hand, it requires starting from population models with a solid design that provide data across the entire range of ages, body sizes, and organ functions.

Simulations based on PopPK analysis allow the most appropriate body size descriptors (TBW, IBW, FFM) to be identified and dosing regimens to be optimized to achieve equivalent exposures in children with and without obesity. In addition, analysis of the probability of achieving the therapeutic target facilitates the selection of the regimen that maximizes efficacy and minimizes the risk of toxicity in this population.

Physiology-based pharmacokinetic modeling, or PBPK modeling, is a mechanistic approach capable of incorporating the physiological changes associated with obesity to describe alterations in drug disposition in obese children. This type of modeling integrates physiological parameters such as organ size and blood flow, along with specific drug properties (e.g., physicochemical and metabolic characteristics) and study design elements such as doses or sampling times. In this way, PBPK models allow for the prediction of pharmacokinetic behaviors and support individualized dosing strategies.

PBPK models have advantages over traditional methods such as PopPK models, as they describe physiological and developmental changes in childhood, allowing the effect of age and body size on drug disposition to be integrated, and they can be used to predict initial PK parameters in obese children and to incorporate the mechanistic information essential for understanding differences in pharmacokinetic behavior.

However, due to their physiological basis, PBPK models require detailed physiological information about the population studied, some of which is still unknown for obese children. Even so, PBPK modeling is a useful tool for simulating the pharmacokinetics and exposure of drugs administered in pediatrics, even when the available clinical data are limited.

This type of study has been conducted in adult patients with obesity to predict the effect of obesity on the Cl of various drugs normalized for various size descriptors. In pediatrics, it has been applied to determine the differences in Vd and Cl between obese and non-obese patients with clindamycin and trimethoprim/sulfamethoxazole, and a recent study has applied the principles of PBPK models to assess the impact of obesity on the PK of amlodipine for children and explore the dosage adjustment required to achieve the same plasma concentrations as in non-obese patients.

Given that there are currently no dosing guidelines for obese pediatric patients with robust clinical evidence, dose adjustments for most drugs must be made with the dual aim of achieving the desired therapeutic effect and minimizing possible adverse effects.

To overcome this gap in knowledge, collaborative efforts between clinicians and researchers should be encouraged to develop modeling tools that elucidate alterations in drug disposition. Likewise, joint efforts between pediatricians and clinical pharmacists are needed to standardize dosing guidelines for overweight and obese children, particularly for high-risk drugs and those with a narrow therapeutic index.