Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05 
Mechanism of action
Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurring activator of carbamoyl phosphate synthetase, the first enzyme of the urea cycle.
Carglumic acid has been shown in vitro to activate liver carbamoyl phosphate synthetase. Despite a lower affinity of carbamoyl phosphate synthetase for carglumic acid than for N-acetylglutamate, carglumic acid has been shown in vivo to stimulate carbamoyl phosphate synthetase and to be much more effective than N-acetylglutamate in protecting against ammonia intoxication in rats. This could be explained by the following observations: i) The mitochondrial membrane is more readily permeable for carglumic acid than for N- acetylglutamate ii) Carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present in the cytosol.

Pharmacodynamic effects
Other studies have been conducted in rats under different experimental conditions leading to increased ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid was shown to decrease blood ammonia levels and increase urea levels in blood and urine, whereas the liver content of carbamoyl phosphate synthetase activators was significantly increased.


Clinical efficacy and safety
In patients with N-acetylglutamate synthase deficiency, carglumic acid was shown to induce a rapid normalisation of plasma ammonia levels, usually within 24 hours. When the treatment was instituted before any permanent brain damage, patients exhibited normal growth and psychomotor development.
In patients with organic acidaemia (neonates and non-neonates), the treatment with carglumic acid induced a quick decrease of ammonia plasma levels, reducing the risk of neurological complications.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabelled and unlabelled product.
Absorption
After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated to be absorbed. At that dose-level, in 12 volunteers given Carbaglu tablets, plasma concentration peaked at 2.6 µg/ml (median; range 1.8-4.8) after 3 hours (median; range 2-4).
Distribution
The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hours after administration followed by a slow phase (terminal half life up to 28 hours).
Diffusion into erythrocytes is non existent. Protein binding has not been determined.
Metabolism
A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, the intestinal bacterial flora may contribute to the initiation of the degradation process, thus leading to a variable extent of metabolism of the molecule. One metabolite that has been identified in the faeces is glutamic acid. Metabolites are detectable in plasma with a peak at 36-48 hours and a very slow decline (half-life around 100 hours).
The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the lungs.
Elimination
After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urine and up to 60% in the faeces.

Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infants to adolescents, treated with various daily doses (7 – 122 mg/kg/day). Their range was consistent with those measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowly declining over 15 hours to levels around 100 ng/ml.