Bioequivalence of a new sustained-release formulation of sodium valproate, valproate modified-release granules, compared with existing sustained-release formulations after once- or twice-daily administration

Abstract

Study objective: To compare the pharmacokinetic properties of valproate modified-release (MR) granules with those of two existing valproate sustained-release (SR) formulations to confirm their bioequivalence.

Design: Two randomized, open-label, two-period crossover studies under fasting conditions, and one open-label, randomized, single-dose, three-period crossover study under fasting and nonfasting conditions. Each study had a 7-day washout interval between periods.

Setting: Three hospitals in France.

Subjects: Healthy male Caucasian volunteers aged 18-35 years (27 subjects in study 1, 24 in study 2, and 24 in study 3).

Intervention: In studies 1 and 2, during two 15-day periods, subjects received either valproate MR granules or an existing valproate SR formulation. In study 3, subjects received only valproate MR granules 500 mg, once with water after a 10-hour fast, once with yogurt after a 10-hour fast, and once 30 minutes after a high-fat morning meal.

Measurements and main results: Blood samples were collected, and pharmacokinetic parameters of valproic acid were determined for single-dose (studies 1-3) and repeated-dose (studies 1 and 2) administration. The 90% confidence intervals (CIs) for area under the concentration-time curve and maximum concentration (C max ) were in the acceptance limits for bioequivalence (i.e., 90% CI 0.80-1.25) after single and repeated doses of valproate MR granules administered once/day or twice/day. Although time to C max was slightly decreased with valproate MR granules, this difference did not induce a significant difference in terms of C max . Valproate MR granule formulation was bioequivalent with existing SR formulations. High-fat breakfast or yogurt did not modify either the bioavailability or pharmacokinetic profile of valproate MR granules. This formulation was well tolerated. The adverse event profile did not differ among the various regimens.

Conclusion: Valproate MR granules, administered once/day or twice/day, may be an attractive alternative to existing SR formulations for patients who have difficulties with swallowing tablets or who favor granules over tablets.