MULTIPLE-DOSE EVALUATION OF THE ABSORPTION CHARACTERISTICS OF DIVALPROEX SODIUM TABLETS, A DELAYED-RELEASE PREPARATION OF VALPROATE, IN HEALTHY-VOLUNTEERS

This was a multiple-dose, open-label, crossover study comparing the ph armacokinetics and safety of 2 twice-daily oral dosage regimens of del ayed-release tablet formulations of divalproex sodium in 16 healthy ma le volunteers. A divided daily dose of 1500mg was administered as eith er regimen A (500mg in the morning and 1000mg in the evening) or regim en B (750mg every 12 hours). On day 6 at steady-state, the 24-hour pla sma concentration profiles and area under the plasma concentration-tim e curve (AUG) values were similar for the 2 regimens. Mean minimum pla sma concentrations were 61.3 and 65.6 mg/L for regimens A and B, respe ctively, and above the recommended therapeutic threshold of 30 to 50 m g/L. Mean maximum plasma concentrations were 127.3 and 129.0 mg/L, res pectively. A diurnal variation in plasma drug concentrations was seen with both regimens and was attributed to delayed absorption of the eve ning dose secondary to digestion of the evening meal. The incidence of adverse events was comparable for the 2 regimens. All adverse events were mild to moderate in severity and comprised mostly transient gastr ointestinal problems and headache.