Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.       Pharmacodynamic properties
Pharmacotherapeutic group: ANTIEPILEPTICS, ATC code: N03AG01.
Valproate is pharmacologically active primarily on the central nervous system.
The drug has an anticonvulsant effect on a very wide range of seizures in animals and epilepsy in humans.
Experimental and clinical studies on valproate suggest 2 types of anticonvulsant effect.
The first is a direct pharmacological effect related to valproate concentrations in the plasma and the brain.
The second appears to be indirect and is probably related to the metabolites of valproate, which remain in the brain, or to changes in neurotransmitters or direct membrane effects. The most widely accepted hypothesis is that of gamma-aminobutyric acid (GABA) levels, which increase following valproate administration.
Valproate reduces the duration of intermediate stages of sleep, with a concomitant increase in slow sleep.

Pharmacokinetic Properties

5.2.       Pharmacokinetic properties
The various pharmacokinetic studies conducted on valproate have shown that:
•      The bioavailability in the blood following oral administration is close to 100%.
•      The volume of distribution is mainly limited to the blood and to the rapid-exchange extracellular fluids. Valproate circulates in the CSF and in the brain.
•      Placental transfer (see section 4.6): Valproate crosses the placental barrier in animal species and in humans: o    in animal species, valproate crosses the placenta to a similar extent as in humans, o    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.
•      The half-life is 15 to 17 hours.
•      Therapeutic efficacy usually requires a minimum serum concentration of 40 to 50 mg/L, with a wide range from 40 to 100 mg/L. If higher plasma levels prove necessary, the expected benefits must be weighed against the risk of occurrence of adverse effects, particularly dose-dependent effects.
However, levels remaining above 150 mg/L require a dose reduction.
•      The steady-state plasma concentration is reached in 3 to 4 days.
•      Valproate is highly protein-bound. Protein binding is dose-dependent and saturable.
•      The major metabolic pathway of valproate is glucuronidation (approximately 40%), mainly via UGT1A6, UGT1A9 and UGT2B7.
•      Valproate is excreted mainly in the urine, following metabolization by glucuronide conjugation and beta-oxidation.
•      Valproate can be dialyzed, but hemodialysis only affects the free fraction of blood valproate (approximately 10%).
•      Valproate does not induce enzymes involved in the metabolic system of cytochrome P 450, in contrast with most other antiepileptics. It therefore does not accelerate its own degradation or that of other substances, such as estrogen-progestogens and oral anticoagulants.

Paediatric population
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.