Prediction and Comparison of Fentanyl Infusion Pharmacokinetics in Obese and Nonobese Children

Objectives: To compare fentanyl infusion pharmacokinetic variables in obese children and nonobese children. Design: A pharmacokinetic simulation study. Setting: We used a semi-physiologically based pharmacokinetic model to generate fentanyl pharmacokinetic variables. Subjects: Simulations of pharmacokinetic variables were based on historical inpatient demographic data in less than 18-year-olds. Interventions: Obese children were defined as children less than 2 years with weight-for-length greater than or equal to 97.7th percentile or body mass index-for-age greater than or equal to 95th percentile for greater than or equal to 2-17-year-olds. Measurements and Main Results: Overall, 4,376 patients were included, with 807 (18.4%) classified as obese children. The majority (52.9%) were male, with a median age of 8.1 years (interquartile range, 4.3-13.0 yr). The differences in total clearance (CL_S), volume of distribution at steady-state values, weight-normalized CL_S, and weight-normalized volume of distribution at steady state were assessed in obese children and nonobese children. Multivariable analyses indicated that obesity was significantly associated with a higher CL_S in obese children greater than 6-year-olds (p < 0.0375). However, there was an 11-30% decrease in weight-normalized CL_S in obese children versus nonobese children in all age groups (p < 0.05). Both volume of distribution at steady state and weight-normalized volume of distribution at steady state increased significantly in obese children compared with nonobese children (p < 0.05). Fentanyl plasma concentration-time profiles of obese children and nonobese children pairs (ages 4, 9, and 15) receiving 1 μg/kg/hr using total body weight were also compared. Steady-state concentrations of the obese children using similar weight-based dosing increased by 25%, 77%, and 44% in comparison to nonobese children 4-, 9-, and 15-year-olds, respectively. Time to steady state and elimination half-lives were two-to four-fold longer in obese children. An additional simulation was conducted for 15-year-old obese children and nonobese children using a fixed dose of 50 μg/hr and it provided similar pharmacokinetic profiles. Conclusions: CL_S may increase less than proportional to weight in obese children greater than 6-year-olds, while volume of distribution at steady state increases more than proportional to weight in all obese children compared with nonobese children. Weight-based dosing in obese children may cause an increase in steady-state concentration while prolonging the time to steady state. Exploring alternative dosing strategies for obese children is warranted.