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

Epilepsy Res. 2002 Mar;49(1):1-10. doi: 10.1016/s0920-1211(02)00007-4.


Valproate formulations, divalproex sodium extended-release (ER) and the traditional divalproex sodium delayed-release (DR) formulations, are 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 I, 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Biological Availability
  • Chemistry, Pharmaceutical
  • Confidence Intervals
  • Cross-Over Studies
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / adverse effects
  • Delayed-Action Preparations / pharmacokinetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Valproic Acid / administration & dosage*
  • Valproic Acid / adverse effects
  • Valproic Acid / blood*
  • Valproic Acid / pharmacokinetics


  • Delayed-Action Preparations
  • Valproic Acid