First-dose and steady-state pharmacokinetics of valproic acid in children with seizures

The serum concentration-time curve of valproic acid was followed in 25 children after single oral doses of the drug and at steady-state. Total body clearance (CL), half-life (t 1/2), and apparent volume of distribution (Vd) were calculated from the terminal portion of the curve and from the area under the serum concentration-time curve (AUC). The CL and Vd were significantly greater at steady-state (0.42 +/- 0.20 ml/min/kg and 0.231 +/- 0.067 L/kg, respectively) than after a single dose (0.32 +/- 0.13 ml/min/kg and 0.191 +/- 0.055 L/kg, respectively). This difference was most pronounced in patients with valproic acid dosage increases in excess of 20% and no change in their concurrent anticonvulsant therapy between the single-dose and steady-state study periods. The t 1/2 was not significantly different between the 2 study periods. There was a significant correlation between age and both CL and Vd after single doses and at steady-state. The t 1/2 did not appear to be age related. These results suggest that the adequacy of the dosage regimen must be determined during maintenance therapy rather than extrapolated from data obtained after a single dose. Re-evaluation of therapy as the child grows older may also be necessary in view of the age-related differences in valproic acid pharmacokinetics which this study has demonstrated.