Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate

Objective: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained releas e formulation of sodium valproate. Subjects and methods: The study was perf ormed using an open, three-period, randomized, crossover design; Twelve hea lthy male volunteers received on three occasions single oral doses of eithe r 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formula tion. A wash-out period of at least 7 days elapsed between the administrati ons. Valproic acid was determined in serum by gas chromatography with flame -ionization detector. Results: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached t heir maxima of 4.3 mu g/ml, 6.8 mu g/ml and 12.8 mu g/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC(0-tz),, and AtTC(0-)infinity a s well as C-max related to each other approximately according to the expect ed ratios of 0.33 : 0.5 : 1. Point estimates and 90% confidence intervals f or the ratios of geometric means of dose-normalized parameters (AUC(0-tz), AUC(0-)infinity, C-max) were included by the acceptance range of 80 - 125%. There were no differences in t(max) as shown by the inclusion of zero in t he 90% confidence interval for the median difference in t(max) between the doses. Conclusion: Parameters determining the extent and rate of absorption (AUC and C-max) increased proportionally with the dose of the new sustaine d release sodium valproate formulation. This pharmacokinetic behavior offer s easier treatment management as dose adjustment is facilitated.