A Nonparametric Population Pharmacokinetic Model of Selumetinib in Pediatric Patients Diagnosed With Neurofibromatosis-I or Plexiform Neurofibromas.
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A twice-daily administration of oral selumetinib (SLT) in the fasted state is the only approved pharmaceutical option for treating inoperable neurofibromatosis type I (NF-1) and plexiform neurofibromas (PN). In children, exposure to SLT is highly variable, and fasting presents a substantial burden. Therapeutic drug monitoring and pharmacokinetic modeling can support individualized therapy accompanied by a more rational alimentary routine. Twenty-eight children diagnosed with inoperable NF-1 or PN were recruited at a major pediatric oncological center. Twenty-two patients donated 156 blood samples in steady state for nonparametric population pharmacokinetic modeling. An equation was developed experimentally for estimating model error. Eleven three-compartment models were compared in terms of statistical performance. Monte Carlo simulations were performed to validate a limited external model using six additional patients and to compare the trough-to-peak SLT concentration ratios simulated for various dosing regimens to develop better control over exposure. A pharmacokinetic model that included total body weight as a covariate provided the best fit between predicted and observed concentrations (r = 0.994) and the best performance statistics. In the first Monte Carlo simulation, measured concentrations fell within the 0.01%-95% (median: 19.7%) quantiles of the simulated ranges. The second simulation revealed that 6-h (q6h), 8-h (q8h), and 12-h (q12h) dosing intervals would yield comparable trough-to-peak concentration ratios, with medians of 0.126 (range: 0.001-0.335), 0.104 (0.000-0.306), and 0.065 (0.000-0.279), respectively. The nonparametric population model provides efficient priors for making individual predictions of SLT concentrations. The simulation did not reveal any disadvantages of q6h or q8h dosing.