Bioavailability of divalproex extended-release formulation relative to the divalproex delayed-release formulation

Abstract

Divalproex sodium extended-release tablet (divalproex-ER) is a novel formulation of the conventional divalproex sodium delayed-release tablet (divalproex). In five multiple-dose studies in healthy subjects (n=82) and epilepsy patients (n=86) the estimates of divalproex-ER/divalproex ratios for steady-state 24 h valproic acid area under the curve (AUC) central values, maximum concentration (C(max)) central values and minimum concentration (C(min)) means had ranges of 0.77-0.97, 0.71-0.87 and 0.78-1.03, respectively. These studies used different divalproex regimens (two, three or four times daily) and meal conditions (fasting, low, medium and high calorie meals). Divalproex-ER was administered once daily. A meta-analysis of divalproex-ER/divalproex relative bioavailability across five studies under different meal conditions and divalproex dosing frequencies was performed. This meta-estimate of relative bioavailability was used to provide dosing recommendations for conversion of patients from divalproex to divalproex-ER. The estimated AUC, C(max) and C(min) divalproex-ER/divalproex ratios (95% confidence interval) were 0.89 (0.85-0.94), 0.79 (0.74-0.84) and 0.96 (0.90-1.02), respectively. The food and divalproex regimen had no effect on the relative bioavailability. While switching from divalproex to divalproex-ER, the divalproex-ER daily dose may have to be increased by an average of 12% (calculated as 1.0/0.89) to achieve comparable plasma exposure. Since the divalproex-ER dosage strengths (250 and 500 mg) are not 12% higher than the divalproex dosage strengths (125, 250 and 500 mg), an 8% to 20% higher divalproex-ER daily dose should be considered for conversion from divalproex to divalproex-ER.