Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers

Valproate formulations, divalproex sodium extended-release (ER) and the traditional divalproex sodium delayed release (DR) formulations. Lire not bioequivalent. This study evaluated if ER QD regimens with 14 and 20% higher daily doses were equivalent to the corresponding DR BID regimens with respect to exposure (AUC) while achieving lower maximum concentration (C-max) and higher minimum concentration (C-min) values. This was a Phase 1. multiple-dose. fasting, randomized, open-label. crossover design study in healthy adult volunteers (n = 36). The two crossover comparisons Of unequal total daily doses were: 1000 mg ER versus 875 mg DR and 1500 mg ER versus 1250 mg DR. For each of 14 and 20% higher ER versus DR dose comparisons, the ER and DR regimens were equivalent with respect to AUC. Furthermore. the ER formulation achieved a lower C-max central value and a higher C-min mean than the corresponding values for the DR formulation. The mean peak-to-trough fluctuations of valproic acid plasma concentrations were 42-48% lower for the ER formulation compared with the DR. The higher ER doses were as well tolerated as DR, with a small number of adverse events that were non-serious in nature and mild in intensity. Therefore, increasing the once-daily ER dose 14-20%. while converting from a total daily DR dose given twice-daily results in equivalent exposure with lower C-max and higher C-min values. (C) 2002 Elsevier Science B.V. All rights reserved.