Personalized Selumetinib Dosing in Pediatric Neurofibromatosis Type 1: Insights From a Pilot Therapeutic Drug...

To evaluate selumetinib exposure using therapeutic drug monitoring (TDM) in pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN), assess interpatient pharmacokinetic variability, and explore the relationship between drug exposure, clinical response, and adverse effects.

In this single-center pilot study, selumetinib plasma concentrations were measured in 22 pediatric NF1 patients receiving treatment for PN. Serial blood sampling was performed at steady-state, and concentrations were quantified using liquid chromatography-tandem mass spectrometry. Noncompartmental modeling was used to estimate pharmacokinetic parameters, including the area under the concentration-time curve (AUC). Clinical outcomes, imaging findings, and treatment-related adverse events were recorded.

Among 24 children included for clinical evaluation, one demonstrated PN regression, 20 had stable disease, and three showed slow progression. Fourteen patients experienced adverse effects, most commonly cutaneous toxicity and creatine-kinase elevation. AUC values were analyzed in 18 patients with stable diseases. Those with adverse events exhibited higher dose-normalized AUCs (4374-13,923 nmol*h/L) than those without toxicity (2961-6011 nmol*h/L). One asymptomatic patient had an unusually high AUC (22,512 nmol*h/L), influencing group distribution. No clear associations were observed between AUC and demographic or routine clinical variables.

Higher selumetinib exposure appears to be associated with treatment-related adverse effects in pediatric NF1 patients. These findings support the potential role of TDM in optimizing selumetinib dosing and provide a preliminary therapeutic AUC range for individualized treatment strategies. Larger multicenter studies are needed to validate these results and refine exposure-guided dosing approaches.