Project Details

Evaluation of the Effects of Childhood Obesity on Drug Dosing

Anil Maharaj, BSc(Pharm), PhD

Summary

BACKGROUND: Obesity-related physiologic changes result in important alterations in drug exposure and dosing. However, there are only a few investigations to inform dosing in children with obesity, resulting in an urgent, unmet public health need. GAP: The proposed research will determine the most important clinical and drug-specific factors that influence drug pharmacokinetics (PK) in obese children and provide an effective dosing strategy for this population. HYPOTHESIS: Fat-free mass and primary drug elimination route (e.g., hepatic vs. renal) will be identified as influential covariates modulating drug PK between obese and non-obese children. METHODS: The study will evaluate plasma concentrations for 8 different drugs collected from obese and non-obese children who received drugs of interest per standard of care. Multi-drug linear-mixed effect and generalized least-square models will be developed to determine the most important clinical and drug-specific factors that influence PK in children with obesity. RESULTS: Obesity status did not influence the relationship between body-size and drug clearance in children. Furthermore, the relationship of body-size and drug clearance was similar between medications with varying drug-specific properties (e.g., molecular weight, pKa, lipophilicity, and primary route of elimination). This finding indicates that changes in body size have a universal effect on drug clearance in children. The predictive performance (bias and precision) of different body-size measures (total body weight, fat-free mass, and normal-fat mass) for estimating drug clearance in children with obesity were similar. Accordingly, since drug clearance is directly related to dosage, our analysis supports the use of total body weight for computing drug dosages in children with obesity. IMPACT: This proposal determined, for the first time in children, the most informative body-size descriptor (i.e., total body weight) for computing drug dosages for children with obesity. The results of this work can provide pediatric practitioners with an effective strategy for dosing their obese patients, lowering the risk of toxicity and therapeutic failures in this population.