Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients

Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t_1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p<0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p<0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.