Free valproic acid: steady-state pharmacokinetics in patients with intractable epilepsy

Free and total valproic acid (VPA) pharmacokinetic evaluation was carried out at steady state in six young epileptics who were also receiving other anticonvulsants. Subjects received their usual morning dose of VPA after an overnight fast. Blood samples for free and total VPA were taken prior to the dose and frequently thereafter for 12 hours. The calculated pharmacokinetic parameters for total VPA and free VPA were: half-lives of 7.5 +/- 1.6 hours and 5.0 +/- 1.5 hours, volumes of distribution of 0.189 +/- 0.038 l/kg and 1.51 +/- 0.98 l/kg, and clearances of 0.30 +/- 0.06 and 3.6 +/- 2.0 ml/min/kg., respectively. There was a strong correlation between percent free VPA and total VPA (r = 0.81) but marked inter- and intra-subject variations were seen. Studies attempting to correlate VPA levels to clinical response must take such data into account.