Model-Informed Dose Selection of Intranasal Epinephrine in Young Children.

Anaphylaxis is a rapid, potentially fatal allergic reaction with a global prevalence of 0.04%-1.8%. Early intramuscular epinephrine administration is recommended. However, fear, pain, cost, or social barriers often delay treatment, leading to poor outcomes. To address these challenges, an intranasal (IN) epinephrine formulation was developed. Pharmacokinetic (PK) data for IN epinephrine are absent in children <4 years (7.5-15 kg) and limited in children ≥4 years. To inform pediatric dosing, we developed a population PK model to support weight-based dosing (≥30 kg, 15-<30 kg, and 7.5-<15 kg) in children. Pooled single-dose IN epinephrine data from six studies (five adults, one pediatric), with 255 subjects and 3564 observations, were analyzed using nonlinear mixed-effects modeling (NONMEM v7.5). Data handling included baseline imputation, exclusion of endogenous concentrations (>4 h), and BLQ management via the M4 method. One- and two-compartment models with allometric scaling by body weight were evaluated. Model performance was assessed using diagnostic plots, objective function value, and prediction-corrected visual predictive checks (pcVPC). Pediatric exposure simulations used CDC-based virtual populations to guide weight-based dosing. A two-compartment model with first-order absorption best described the data, with acceptable relative standard error <30% and no evidence of model misspecification. pcVPC demonstrated good agreement across adult and pediatric subgroups. Simulations indicated that the pediatric doses of 2 mg (≥30 kg) and 1 mg (15-<30 kg) achieved exposure comparable to the adult 2 mg reference, supporting the dosing strategy. Model-informed simulations support weight-based IN epinephrine dosing in young children, addressing a critical gap in anaphylaxis management.