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

✍ Scribed by Sandeep Dutta; Yiming Zhang

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 120 KB
• Volume: 25
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.420

✦ Synopsis

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. Copyright © 2004 John Wiley & Sons, Ltd.