Population Pharmacokinetics of Dupilumab in Adults, Adolescents, and Children With Eosinophilic Esophagitis.

Dupilumab, a fully human monoclonal antibody that blocks key drivers of type 2 inflammation, is approved across 8 diseases, including eosinophilic esophagitis. Subcutaneous dupilumab 300 mg weekly improved outcomes vs. placebo in adults (aged ≥ 18 years) and adolescents (aged ≥ 12 to < 18 years) during the phase III LIBERTY EoE TREET study (NCT03633617). The phase III EoE KIDS study (NCT04394351) demonstrated efficacy of a weight-tiered, higher exposure dupilumab dose approximating 300 mg weekly exposure in TREET vs. placebo in children aged ≥ 1 to < 12 years. To characterize dupilumab pharmacokinetics, inform clinical trial design, and optimize posology, a population pharmacokinetic model was developed using dupilumab concentration data from 6 single-dose studies in healthy adults and 3 eosinophilic esophagitis clinical trials. Healthy volunteer data were used to construct a stable base model; incorporation of patient data allowed estimation covariate effects for the disease population. Observational data from up to 52 weeks of treatment in eosinophilic esophagitis trials validated model performance. Significant effects were identified for body weight on clearance and volume of distribution, including time-varying weight in children and adolescents, and of albumin on clearance; age was not a significant covariate. Simulations identified alternative dupilumab regimens for patients weighing ≥ 5 to <15 kg (200 mg every 3 weeks) and ≥ 40 to <60 kg (300 mg weekly) with improved exposure matching to the 300 mg weekly dose in TREET. The final model was used to inform regulatory approval and potential future clinical trial design.