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Model-Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients

Francois Pierre Combes1, Heidi J Einolf1, Neva Coello2

  • 1Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

CPT: Pharmacometrics & Systems Pharmacology
|March 10, 2020
PubMed

Insights

Everolimus, used for tuberous sclerosis complex (TSC)-associated seizures, shows promise for younger children. Modeling suggests the 6 mg/m² dose may effectively reduce seizures in infants and toddlers aged 6 months to 2 years.

Area of Science:

  • Pharmacology and Therapeutics
  • Pediatric Neurology
  • Computational Modeling

Background:

  • Tuberous sclerosis complex (TSC) causes refractory partial-onset seizures, often starting in infancy.
  • Current treatment guidelines for everolimus in TSC-associated seizures apply to patients aged 2 years and older.
  • There is a need to evaluate treatment efficacy in younger children (6 months to 2 years) with TSC.

Purpose of the Study:

  • To predict the efficacy of everolimus in children aged 6 months to 2 years with TSC-associated seizures using a modeling and simulation (M&S) approach.
  • To extrapolate pharmacokinetic (PK) exposure (trough plasma concentration, Cmin) and pharmacodynamic (PD) effects (reduction in seizure frequency, RSF) for everolimus in this younger pediatric population.
  • To support potential expanded use of everolimus in younger children with TSC.

Main Methods:

  • Development of a physiologically based pharmacokinetic (PBPK) model using Simcyp software to predict everolimus Cmin in pediatric patients.
  • Integration of the PK model with population pharmacodynamic (PopPD) and linear mixed-effects models to predict seizure frequency reduction (RSF).
  • Validation of the M&S approach using adult data before predicting efficacy in children aged 6 months to 2 years.

Main Results:

  • The M&S approach successfully predicted everolimus exposure and efficacy.
  • Simulated trough concentrations (Cmin) for everolimus at 6 mg/m² were within the target range for children aged 6 months to 2 years.
  • The models predicted a significant reduction in seizure frequency (up to 77.8% RSF) in this younger pediatric population.

Conclusions:

  • Everolimus at a dose of 6 mg/m² is predicted to be efficacious for treating TSC-associated partial-onset seizures in children aged 6 months to 2 years.
  • The M&S approach provides valuable insights for optimizing everolimus dosing in young children with TSC.
  • These findings support the potential for everolimus as a treatment option in a broader pediatric age range for TSC.

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