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

• Published in: Epilepsy research 2002-03, Vol.49 (1), p.1-10
• Main Authors: Dutta, Sandeep, Zhang, Yiming, Selness, Daniel S., Lee, Lillian L., Williams, Laura A., Sommerville, Kenneth W.
• Format: Article
• Language: English
• Subjects: Adult; Analysis of Variance; Anticonvulsants. Antiepileptics. Antiparkinson agents; Area Under Curve; Bioequivalence; Biological and medical sciences; Biological Availability; Chemistry, Pharmaceutical; Confidence Intervals; Cross-Over Studies; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - adverse effects; Delayed-Action Preparations - pharmacokinetics; Divalproex sodium; Extended-release; Female; Humans; Male; Medical sciences; Middle Aged; Neuropharmacology; Pharmacokinetics; Pharmacology. Drug treatments; Valproate; Valproic Acid - administration & dosage; Valproic Acid - adverse effects; Valproic Acid - blood; Valproic Acid - pharmacokinetics
• ISSN: 0920-1211; 1872-6844
• 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.