DEPACON exists as the valproate ion in the blood. 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).

Bioavailability

Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent C_max, C_min, and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary with the formulation used. These differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

Administration of DEPAKOTE (divalproex sodium) tablets and IV valproate (given as a one hour infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, C_max, C_min at steady state, as well as after the first dose. The T_max after IV DEPACON occurs at the end of the one hour infusion, while the T_max after oral dosing with DEPAKOTE occurs at approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence between DEPACON and DEPAKOTE up to the maximum recommended dose of 60 mg/kg/day can be assumed. The AUC and C_max resulting from administration of IV valproate 500 mg as a single one hour infusion and a single 500 mg dose of DEPAKENE syrup to 17 healthy male volunteers were also equivalent.

Patients maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided doses every 6 hours) as oral DEPAKOTE (divalproex sodium) alone (n = 24) or with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic acid when switching from oral DEPAKOTE to IV valproate (1-hour infusion).

Eleven healthy volunteers were givensingle infusions of 1000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4-period crossover study. Total valproate concentrations were measured; unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8 mg/kg/min), mean C_max was 145 ± 32 m g/mL, while after the 60 minute infusions, mean C_max was 115 ± 8 mg/mL. Ninety to 120 minutes after infusion initiation, total valproate concentrations were similar for all 4 rates of infusion. Because protein binding is nonlinear at higher total valproate concentrations, the corresponding increase in unbound C_max at faster infusion rates will be greater.

Distribution

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mg/mL to 18.5% at 130 mg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS - Drug Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

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