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

PURPOSE: To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin.

METHODS: A phenytoin pharmacokinetic model was used in the Simcyp™ population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model.

RESULTS: Loading with doses of 18mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10μg/mL), therapeutic in 62/100 (C2h 10-20μg/mL), and supra-therapeutic in 16/100 (C2h>20μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20mg/kg increased the mean C2h from 16.0 to 17.9μg/mL, and the mean AUC from 145 to 162μg/mL/h. A C2h>30μg/mL was predicted in 4% and 8% of children in the 18 and 20mg/kg doses, with 3% predicted to have a C2h>40μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20mg/kg loading) gives the highest percentages of 10-20μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%.

CONCLUSION: Use of PBPK modelling suggests that children receiving the 20mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate.