Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: anti-epileptics/fatty acid derivatives/antipsychotics, ATC code: N03AG01/N05 AX.

Valproic acid is an anti-epileptic with no structural similarity to other anticonvulsant drugs.
Potentiation of GABA-mediated inhibition caused by a presynaptic effect on GABA metabolism and/or a direct postsynaptic effect on the ion channels of the neuronal membrane are assumed to be the mechanism of action of valproic acid.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
After oral administration, valproic acid and its sodium salt are rapidly and almost completely absorbed in the gastrointestinal tract.

The time taken to reach the peak serum concentration depends on the pharmaceutical form:
Peak serum concentrations after one Depalept Chrono 500 mg prolonged-release tablet are reached within 6.3 ± 0.95 hours.

Distribution
The mean therapeutic range of serum concentrations is reported as 50−100 mg/l. Above 100 mg/l, an increase in undesirable effects to the point of intoxication should be expected. Steady-state serum levels are usually reached within three to four days.

Cerebrospinal fluid concentrations of valproic acid are 10 % of the respective serum concentration.

The volume of distribution depends on age and is usually 0.13−0.23 l/kg of body weight or, in younger people, 0.13−0.19 l/kg of body weight.

90−95% of valproic acid is bound to plasma proteins, primarily albumin. At higher doses, protein binding decreases. Plasma protein binding is lower in elderly patients and in patients with impaired renal or hepatic function. In one study, higher levels of free active substance (8.5 % to over 20 %) were seen in patients with significantly impaired renal function. The total valproic acid concentration, consisting of a free and a protein-bound form, may be largely unchanged in patients with hypoproteinaemia, but can also be reduced as a result of increased metabolism of the free form.

Biotransformation
Biotransformation takes place through glucuronidation as well as beta-, omega- and omega-1- oxidation. The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7. About 20 % of the administered dose is found as ester glucuronide in the urine after renal excretion. There are more than 20 metabolites, whereby those of omega- oxidation are regarded as hepatotoxic. Less than 5 % of the valproic acid dose appears unchanged in the urine.

The main metabolite is 3-keto-valproic acid, of which 3−60 % is found in the urine. This metabolite has an anticonvulsive effect in mice. In humans, the effect has not yet been clarified.

In contrast to other anti-epileptics, valproic acid has no liver enzyme-inducing effect and thus does not promote its own metabolism.

Elimination
In one study, plasma clearance was 12.7 ml/min in patients with epilepsy. In healthy subjects, it is 5−10 ml/min. If enzyme-inducing anti-epileptics are taken, it increases.

In healthy subjects, the plasma half-life of valproic acid in healthy subjects is 17.26 ± 1.72 hours.

In combination with other medicinal products (e.g. primidone, phenytoin, phenobarbital and carbamazepine), the half-life falls to between 4 and 9 hours depending on enzyme induction. Newborn infants and children up to 18 months old exhibit a plasma half-life of between 10 and 67 hours. The longest half-lives have been observed immediately after delivery. Over the age of 2 months, the results become more like those of adults.

Linearity/non-linearity
There is an almost linear relationship between the dose of Depalept Chrono and the serum concentration.

Specific patient groups
In patients with liver disease, the half-life is prolonged. In cases of overdose, half-lives of up to 30 hours have been observed.

Paediatric patients
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.

When the volume of distribution increases in the third trimester of pregnancy, hepatic and renal clearance increase, with a potential fall in the serum concentration despite a constant dose.

It should also be noted that plasma protein binding can change and the proportion of free (therapeutically active) valproic acid can increase during the course of a pregnancy.

Placental transfer/Excretion into breast milk (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.

Valproate is excreted in human milk with a concentration ranging from 1 % to 10 % of maternal serum level.

Bioavailability
A bioavailability study in 12 healthy subjects (20−45 years old, male) conducted in 1985 compared a dose of two Depalept Chrono 500 mg prolonged-release tablets in the morning with a dose of one Depalept 500 mg film-coated tablet in the morning and one in the evening, and produced the following results at steady state (day 10):


Depalept Chrono              Depalept Chrono 500 mg
500 mg prolonged-            gastro-resistant film- release tablets              coated tablets
(1 x 1000 mg/day)            (2 x 500 mg/day)
Minimum plasma concentration               44.7 ± 9.6 µg/ml             54.3 ± 16.0 µg/ml (Cmin):
Peak plasma concentration                  81.6 ± 15.8 µg/ml            95.2 ± 15.8 µg/ml (Cmax):


Time to peak plasma concentration      6.58 ± 2.23 h                  3.08 ± 0.5 h (tmax):
Area under concentration time curve    1486 ± 249 µg∙h/ml             1572 ± 286 µg∙h/ml (AUC):
Values are given as mean values and ranges.