Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pediatric Pharmacology
• Computational Modeling in Medicine

Background:

• Phenytoin is an anticonvulsant medication used to treat epilepsy.
• Determining optimal intravenous loading doses in pediatric populations is crucial for efficacy and safety.
• Population-based pharmacokinetic modeling offers a predictive approach to guide dosing strategies.

Purpose of the Study:

• To predict serum phenytoin concentrations using a physiologically based pharmacokinetic (PBPK) modeling system.
• To evaluate two different intravenous loading doses of phenytoin in pediatric patients.
• To assess the risk of sub-therapeutic, therapeutic, and supra-therapeutic serum levels.

Main Methods:

• Utilized a phenytoin pharmacokinetic model within the Simcyp population-based ADME simulator.
• Simulated 100 children aged 2-10 years receiving intravenous phenytoin at 18 mg/kg and 20 mg/kg.
• Employed visual checks to validate the predictive accuracy of the PBPK model.

Main Results:

• The 18 mg/kg loading dose resulted in sub-therapeutic levels in 22%, therapeutic in 62%, and supra-therapeutic in 16% of children.
• The 20 mg/kg loading dose showed a shift towards supra-therapeutic levels (15% sub-therapeutic, 59% therapeutic, 26% supra-therapeutic).
• A 10 mg/kg maintenance dose achieved therapeutic concentrations in 93% of children with initially sub-therapeutic levels after a 20 mg/kg loading dose.

Conclusions:

• PBPK modeling indicates a slightly increased risk of supra-therapeutic phenytoin levels with a 20 mg/kg intravenous loading dose in children.
• Therapeutic drug monitoring is recommended to manage serum concentrations effectively.
• The suggested dosing regimen aligns with British National Formulary for Children (BNFc) recommendations.