Depakote

[Divalproex]

Bioavailability of DEPAKOTE ER Tablets Relative to DEPAKOTE When DEPAKOTE ER Dose is 8 to 20% Higher
Study Regimens Relative Bioavailability
Population DEPAKOTE ER vs. DEPAKOTE AUC24 Cmax Cmin

Healthy Volunteers (N= 35) 1000 & 1500 mg DEPAKOTE ER vs. 875 & 1250 mg DEPAKOTE 1.059 0.882 1.173

Patients with epilepsy on concomitant enzyme-inducing
antiepilepsy drugs (N= 64)
1000 to 5000 mg DEPAKOTE ER vs.
875 to 4250 mg DEPAKOTE 1.008 0.899 1.022

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Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate bioavailability when converting between DEPAKOTE and DEPAKOTE ER.

Distribution Protein Binding:

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 µg/ mL to 18.5% at 130 µg/ 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).

CNS Distribution:

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

Metabolism

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial -oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.

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