Valproic acid Other names: Sodium valproate Valproate acid Divalproex sodium

Sodium valproate and valproic acid are anti-convulsants.

The most likely mode of action for valproate is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

In certain in-vitro studies it was reported that valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that valproate does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100 mg/litre (278-694 micromol/litre). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

Metabolism

The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7.

The half-life of valproate is usually reported to be within the range of 8-20 hours. It is usually shorter in children.

Interaction with oestrogen-containing products

Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.

The prolonged (or modified) release granules formulation of valproate reduces peak concentration and ensures more even plasma concentrations throughout the day, comparable with other modified release valproate formulations.

Compared with immediate release forms of valproate, it is characterized at an equivalent dose by:

• a similar bioavailability,
• a lower C_max (decrease of approximately 25%),
• a relatively stable plateau between 4 and 14 hours after administration.
• Following twice daily administration, the range of plasma fluctuations is approximately reduced by half.

Steady-state pharmacokinetic data indicate that the peak concentration (C_max) and trough concentration (C_min) of valproate prolonged (or modified) release granules lie within the effective therapeutic range of plasma levels found in pharmacokinetic studies with valproate enteric coated tablets.

In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of valproate prolonged (or modified) release granules make the measurement of plasma levels less dependent upon time of sampling.

The peak plasma level is achieved approximately 7 hours after administration, with an elimination half-life of approximately 16 hours.

This pharmacokinetic profile is not affected by taking the drug with food.

There are no pre-clinical data.