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

Batchelor, Hannah and Appleton, Richard and Hawcutt, Daniel B. (2015) Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software. Seizure, 33. pp. 8-12. ISSN 1532-2688 (https://doi.org/10.1016/j.seizure.2015.10.006)

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Abstract

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 SimcypTM population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20 mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Results: Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2 h post infusion (C2h) <10 μg/mL), therapeutic in 62/100 (C2h 10-20 μg/mL), and supra-therapeutic in 16/100 (C2h > 20 mg/mL). Loading with 20 mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h > 30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h > 40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5 mg/kg (intravenous) given at 12 h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10 mg/kg will achieve therapeutic concentrations in 93%. Conclusion: Use of PBPK modelling suggests that children receiving the 20 mg/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.

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