Valproic acid dosages necessary to maintain therapeutic concentrations in children

Steady-state plasma valproic acid (VPA) concentrations were measured in 118 pediatric inpatients taking VPA. There was a significant (p less than 0.0001) inverse correlation between the daily VPA dosage and the VPA dose ratio (concentration/dose or 1/clearance). The VPA dose ratio was significantly lower in patients taking VPA in combination with phenobarbital (p less than 0.01), carbamazepine (p less than 0.05), or multiple other antiepileptic drugs (p less than 0.0001), compared with those on VPA monotherapy. Neither age nor sex had any influence on VPA dose ratios. No significant (p greater than 0.1) correlation was found between VPA doses and concentrations in children on monotherapy. The distribution of VPA dose concentrations suggests that children, especially those on VPA polytherapy, require higher than recommended pediatric VPA maintenance doses (greater than 60 mg/kg/day) to maintain concentrations greater than 50 mg/L. Results also indicate that at higher concentrations (greater than 80 mg/L), increasing doses may produce less than proportional increases in total VPA concentration.