Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Anti-epileptics
ATC Code: N03A F01

Carbamazepine is a dibenzoazepine derivative. Pharmacologically it shares properties with phenytoin.
The mechanism of action is not fully understood to date. Like phenytoin, carbamazepine inhibits synaptic transmission and thereby reduces the propagation of convulsive discharges.
In higher concentrations, carbamazepine decreases post-tetanic potentiation.
Pain relief in trigeminal neuralgia is probably attributable to an inhibition of synaptic stimulus transmission in the spinal nucleus of the trigeminal nerve.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Absorption
Carbamazepine is relatively slowly and almost completely reabsorbed after oral administration (depending on the dosage form).

The absorption half-life averages 8.5 h and shows large intra- and inter-individual variations (ranging from approx. 1.72 to 12 h).

Peak plasma levels after a single dose are reached (depending on the dosage form) after 4 to 16 hours in adults (very rarely up to 35 h) and after about 4 - 6 h in children. Plasma levels are not linearly related to dose and show a flat course in the higher dosage region.

Peak plasma levels are achieved faster after administration of the suspension than after normal tablets or prolonged-release tablets.

Plasma levels after administration of prolonged-release tablets are lower than after non- prolonged release ones.

The steady state is reached after 2 to 8 days. There is no strict correlation between the dose of carbamazepine and the steady state plasma concentration.
With a dosage interval of 8 or 12 h, fluctuations in the plasma levels of carbamazepine and its metabolite carbamazepine-10,11-epoxide in the steady state are small.

In terms of therapeutic and toxic plasma concentrations, it is stated in the literature that a seizure-free state can be achieved with plasma levels of 4 to 12 µg/mL. If a level of 20 µg/mL is exceeded, the clinical picture worsens. Relief of pain in trigeminal neuralgia is achieved with plasma concentrations of 5 to 18 µg/mL.
The threshold concentration for the occurrence of adverse reactions is approx. 8 to 9 µg/mL.

Distribution
The volume of distribution in humans is given as 0.8 - 1.9 L/kg.
Between 70% and 80% of carbamazepine is bound to plasma proteins. The proportion of free carbamazepine is constant up to a concentration of 50 µg/mL. Between 48% and 53% (approx. 0.74 L/kg) of carbamazepine-10,11-epoxide, the pharmacologically active metabolite, is bound to plasma proteins.
Pharmacokinetic interactions should be expected, see section 4.5.

The carbamazepine concentration in cerebrospinal fluid is about 33% of the corresponding plasma concentration.
Salivary carbamazepine levels correspond to the level of the free parent substance and show good correlation with plasma levels (about 20 - 30%). If multiplied by 4, salivary concentrations can be used to estimate plasma levels during the therapy.
Carbamazepine crosses the placental barrier and passes into breast-milk (about 58% of plasma concentration). The concentrations found in the plasma of breast-fed infants correspond to those in their mothers’ milk.

Biotransformation
Carbamazepine undergoes oxidation, deamination, hydroxylation and finally esterification with glucuronic acid in the liver.
To date, seven metabolites of carbamazepine have been found in human urine. The pharmacologically inactive metabolite trans-10,11-dihydroxy-10,11-dihydrocarbamazepine accounts for the largest proportion. Only 0.1% to 2% represents the metabolite carbamazepine 10,11-epoxide, which itself has anticonvulsant activity.



Elimination
The half-life of elimination of carbamazepine from plasma after a single dose is approx. 36 hours (Range: 18 – 65 h).
On long-term administration, the half-life falls by about 50% (10 - 20 hours) due to enzyme induction. In combination with other antiepileptics, the half-life is shorter (average 6 - 10 h) than with monotherapy (11 - 13 h); half-lives are shorter in children than in adults, whilst longer in neonates than in infants

Plasma clearance in healthy subjects is approximately 19.8 ± 2.7 mL/h/kg, in patients receiving monotherapy about 54.6 ± 6.7 mL/h/kg and in those on combination therapy around 113.3 ± 33.4 mL/h/kg

About 72% of a single oral dose is excreted by the kidneys in the form of metabolites. The remaining 28% is excreted via the faeces, some as unchanged carbamazepine. Only 2 - 3% of the amount excreted in the urine is unchanged carbamazepine.

Bioavailability/bioequivalence
A bioavailability study conducted on 12 subjects (23 – 31 years [mean 27], male) in 1995 showed the following data after a single dose of 600 mg carbamazepine as 1 prolonged release Timonil 600 retard or 1½ prolonged-release tablets of the reference preparation on an empty stomach:

Test preparation                Reference preparation
Timonil 600 retard
Peak plasma concentration
(Cmax): µg/mL                    3.4 ± 0.6                       3.1 ± 0.5 Time to peak plasma concentration
(tmax): h                        27.7 ± 7.9                      27.3 ± 8.6 Area under the concentration-time curve         259 ± 73.5                      240 ± 60.3 (AUC0-∞): µg/mL · h

Figures given as mean and range

Medium serum concentration of Timonil 600 retard in comparison to a reference product in a concentration-time-diagram:


Timonil 600 retard
Reference preparation
Plasma concentration (μg/ml)


Time (h)