Depakote

[Divalproex]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Pharmacodynamics

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

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Pharmacokinetics Absorption/ Bioavailability

The absolute bioavailability of DEPAKOTE ER TABLETS administered as a single dose after a meal was approximately 90% relative to intravenous infusion. When given in equal total daily doses, the bioavailability of DEPAKOTE ER is less than that of DEPAKOTE (divalproex sodium delayed-release tablets).

In five multiple-dose studies in healthy subjects (N= 82) and in subjects with epilepsy (N= 86), when administered under fasting and nonfasting conditions, DEPAKOTE ER given once daily produced an average bioavailability of 89% relative to an equal total daily dose of DEPAKOTE given BID, TID, or QID. The median time to maximum plasma valproate concentrations (Cmax) after DEPAKOTE ER administration ranged from 4 to 17 hours. After multiple once-daily dosing of DEPAKOTE ER, the peak-to-trough fluctuation in plasma valproate concentrations was 10-20% lower than that of regular DEPAKOTE given BID, TID, or QID.

Conversion from DEPAKOTE to DEPAKOTE ER:

When DEPAKOTE ER is given in doses 8 to 20% higher than the total daily dose of DEPAKOTE, the two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses of DEPAKOTE were compared to 8 to 20% higher once-daily doses of DEPAKOTE ER. In these two studies, DEPAKOTE ER and DEPAKOTE regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of bioavailability). Additionally, valproate Cmax was lower, and Cmin was either higher or not different, for DEPAKOTE ER relative to DEPAKOTE regimens (see following table).

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