PHARMACOKINETICS OF VALPROIC ACID IN PATIENTS WITH JUVENILE MYOCLONICEPILEPSY ON MONOTHERAPY

Two different doses of sodium valproate (VPA), 500 mg b.i.d. and 1,000 mg b.i.d. as enteric-coated tablets, were used in this randomized, do uble-blind, cross-over monotherapy study of 16 patients with juvenile myoclonic epilepsy. Observation time was 6 months on each dose and inc luded admittance for a 12-h serum concentration-time curve. There was a nonlinear relation between dose and concentration, with a negative d eviation from the linear relation for total concentration and a positi ve deviation for the unbound fraction. Clearance for total concentrati on increased during high-dose treatment, but intrinsic clearance did n ot differ between doses. We measured the variation of repeated total a nd unbound VPA concentrations in up to 6 monthly samples on each dose. The coefficient of variation was 20.7% for total and 29.9% for unboun d concentration on the lower dose, and 16.5% for total and 28.5% for u nbound concentration on the higher dose. This difference between doses is not statistically significant. There was good correlation between the concentration taken before morning dose and AUC for one dose inter val, especially during high dose? but the morning concentration was no t the trough level. We conclude that the pharmacokinetic requirements for therapeutic drug monitoring of VPA are established.