Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Fatty acid derivatives
ATCcode: N03AG01
The mode of action of valproic acid in epilepsy is not fully understood but may involve an elevation of gamma-amino butyric acid levels in the brain.
In certain in-vitro studies, it was reported that sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed, the effect of sodium 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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

The reported effective therapeutic range for plasma valproic acid levels is 40–100 mg/L (278–694 μmol/L). This reported range may depend on time of sampling and presence of co- medication.


Per definition, with intravenous injection the bioavailability amounts to 100. The half-life is 8–20 h in most patients but can in exceptional cases be considerable lower. It is usually shorter in children.
Above the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. In paediatric patients below the age of 10 years, the systemic clearance of valproate varies with age. In neonates and infants up to 2 months of age, valproate clearance is decreased when compared to adults and is lowest directly after birth. In a review of the scientific literature, valproate half-life in infants under two months showed considerable variability ranging from 1 to 67 hours. In children aged 2-10 years, valproate clearance is 50% higher than in adults.
In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free serum valproic acid levels.
Steady-state concentration is normally achieved after treatment in 3 - 5 days. A satisfactory effect is most often achieved at 40 – 100 mg/litre (278 – 694 micromol/litre), but the patient’s overall situation must be considered. The reported range may depend on time of sampling and presence of co-medication. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.
The pharmacological (or therapeutic) effects of Orfiril injection may not be clearly correlated with the total or free (unbound) plasma valproic acid levels. The CFS concentration is up to 10% of the plasma concentration. The percentage of free (unbound) drug is usually between 6 and 15% of the total plasma levels. Sodium valproate is metabolised to a great extent and is excreted in the urine as conjugated metabolites.
Placental transfer (see section 4.6)
Valproate crosses the placental barrier in animal species and in humans:
• In animal species, valproate crosses the placenta to a similar extent as in humans.
• In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery.
Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Valproic acid passes into breast milk but is not likely to influence the child when therapeutic doses are used.