Purpose Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N‐ desmethyl metabolite, evaluated exposure–safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m 2 bid based on body surface area (BSA) in this patient population. Methods Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers ( n  = 391), adult oncology patients ( n  = 83) and pediatric patients with NF1-PN ( n  = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure–safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m 2 bid). Results Selumetinib and metabolite concentration–time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0–12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea. Conclusion Findings support continuous selumetinib 25 mg/m 2 bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.