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.
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.


METHODS
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.


METHODS
Three hospitals in France.


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


METHODS
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.


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.


CONCLUSIONS
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.
Dulac
Olivier
O
Neuropediatric Department, Hôpital Necker, Paris, France.
Alvarez
Jean-Claude
JC
D000328:Adult; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004435:Eating / Q000502:physiology; D041981:Gastrointestinal Tract / Q000187:drug effects; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D013678:Technology, Pharmaceutical / Q000379:methods; D013810:Therapeutic Equivalency; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D014635:Valproic Acid