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Valproic acid pharmacokinetics in children: III. Very high dosage requirements
R L Kriel1, J H Fischer, J C Cloyd
1Division of Pediatric Neurology, St. Paul-Ramsey Medical Center, MN 55101.
Insights
Children needing high doses of valproic acid (VPA) for seizure control were lighter and had altered pharmacokinetics. Adjusting co-medications significantly reduced VPA dosage requirements, suggesting drug interactions impact VPA levels.
Area of Science:
- Pediatric Neurology
- Clinical Pharmacology
Background:
- Valproic acid (VPA) is a widely used antiepileptic drug.
- Some children require unusually high VPA doses to reach therapeutic serum concentrations.
- Understanding factors influencing VPA dosage is crucial for effective treatment.
Purpose of the Study:
- To investigate the characteristics and pharmacokinetic profiles of children requiring very high VPA doses.
- To explore the impact of concomitant antiepileptic drugs on VPA dosage requirements.
Main Methods:
- Retrospective study of nine children with poorly controlled seizures on high-dose VPA.
- Comparison of anthropometric data and pharmacokinetic parameters (clearance, volume of distribution, free fraction) with a control group.
- Analysis of VPA dosage adjustments after withdrawal of co-medications in a subset of patients.
Main Results:
- Children requiring high-dose VPA were significantly smaller (lighter, shorter, less body surface area).
- Increased total and intrinsic clearance, distribution volume, and VPA free fraction were observed in the high-dose group.
- Elimination of co-medications reduced VPA clearance and dosage requirements by over 50% in three patients.
Conclusions:
- Very high valproic acid dosages are sometimes necessary to achieve therapeutic serum concentrations in specific pediatric populations.
- Pharmacokinetic alterations, including increased clearance and distribution, contribute to high VPA dose requirements.
- Concomitant antiepileptic drugs significantly influence VPA dosage needs, highlighting the importance of managing polypharmacy.
Abstract:
Nine children were studied who required very high doses of valproic acid (VPA) (63.6-105 mg/kg/day) in order to achieve VPA serum concentrations between 50-100 micrograms/ml. These nine children had poorly controlled seizures and were receiving other antiepileptic drugs at the time of this study. The children with very high dose requirements were significantly lighter, shorter, and had less body surface area than the control group. Of the pharmacokinetic parameters studied, total and intrinsic clearance, distribution volume, and valproic acid free fraction were significantly increased in the very high dose group. In three patients who were investigated after co-medications were eliminated, clearances and dosage requirements decreased by more than 50%. We concluded that very high VPA dosages are sometimes required to achieve therapeutic serum drug concentrations and that this therapy occasionally improves seizure control. There were no adverse effects of very high dose therapy that required dosage reduction.