Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism, various alimentary tract and metabolism products, ATC code: A16AX12

Mechanism of action
Trientine is a copper-selective chelator that enhances systemic elimination of divalent copper by forming a stable complex that is readily excreted by the kidneys. Trientine is a chelator with a polyamine-like structure and copper is chelated by forming a stable complex with the four constituent 5
nitrogens in a planar ring. Thus, the pharmacodynamic action of trientine is dependent on its chemical property of chelating copper and not on its interaction with receptors, enzyme systems or any other biological system that might differ between species. Trientine may also chelate copper in the intestinal tract and so inhibit copper absorption.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
The bioavailability of trientine capsules in human beings has not been established. Based on preclinical data, the mechanism of absorption and the high first pass effect, it is expected that trientine bioavailability is low and highly variable following oral administration. Clinical studies showed that trientine is absorbed with tmax occurring between 0.5 and 6 hours post-dose in healthy volunteers and patients. Exposure to trientine is highly variable between subjects, with a variation of up to 60%.
The intake of food within 30 minutes prior to trientine administration delays the time to peak concentrations by 2 hours and reduces the extent of absorption of trientine by approximately 45%.
Distribution
Trientine has low human plasma protein binding and is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney in the rat.

Biotransformation
Trientine is acetylated in two major metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT). Clinical data in healthy subjects indicate that the plasma exposure to the MAT metabolite is approximately 3 times that of unchanged trientine, while exposure to the DAT metabolite is slightly lower compared to trientine. The metabolites of trientine have Cu-chelating properties, however the stability of these Cu-complexes is low due to the introduction of the acetyl groups. Clinical data in healthy volunteers suggest limited contribution of chelating activity by the MAT and DAT metabolites.The extent of MAT and DAT’s contribution to the overall effect of Cufence on copper levels in Wilson’s Disease patients remains to be determined.

Trientine is metabolised by acetylation via spermidine/spermine N-acetyltransferase and not via N-acetyltransferase 2.

Elimination
After absorption trientine and its metabolites are rapidly excreted in the urine, either bound to copper or unbound. The unabsorbed fraction of orally administered trientine is bound to intestinal copper and eliminated through faecal excretion.
The elimination half-life of trientine is approximately 4 hours (mean t1/2 of 3.8 ± 1.3 hours measured at steady state in WD patients and 4.4 ± 4.7 hours measured after a single dose in healthy volunteers). The elimination half-lives of the two metabolites were 14.1 ± 3.7 hours for MAT and 8.5 ± 3.0 hours for DAT after a single dose administration of trientine in healthy subjects.
Special populations
Age /Gender/ Body weight
Data from clinical studies conducted in adult healthy subjects indicate that age, gender and body weight do not seem to influence the pharmacokinetics of trientine.
Ethnicity
No pharmacokinetic analysis has been performed on interethnic differences.