CUPRIOR Film-coated tablet Ref.[9243] Active ingredients: Trientine

Absorption

The absorption of trientine following oral administration is low and variable in patients with Wilson disease. The pharmacokinetic profile of Cuprior has been evaluated after a single oral dose of 450, 600 mg and 750 mg trientine in healthy male and female subjects. Plasma levels of trientine rose rapidly following administration with the median peak level reached after 1.25 to 2 hours. The trientine plasma concentration then declined in a multiphasic manner, initially rapidly, followed by a slower elimination phase. The overall pharmacokinetic profiles were similar between males and females, although males had higher levels of trientine.

Distribution

Little is known on the distribution of trientine in organs and tissues.

Biotransformation

Trientine is acetylated in two majors metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT). MAT may also participate to the overall clinical activity of Cuprior, however the extent of MAT to the overall effect of Cuprior on copper levels remains to be determined.

Elimination

Trientine and its metabolites are rapidly excreted in the urine, although low levels of trientine could still be detected in the plasma after 20 hours. Unabsorbed trientine is eliminated through faecal excretion.

Linearity/non-linearity

Plasma exposures in humans have shown a linear relationship with oral doses of trientine.

Preclinical data obtained with trientine have shown adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use as follows:

Repeat dose toxicity

In mice administered in drinking water, trientine displayed increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration. Hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolisation. The NOAEL was established at approximately 92 mg/kg/day for males and 99 mg/kg/day for females. In rats administered oral trientines doses, up to 600 mg/kg/day for 26 weeks, histopathology revealed a dose-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar wall. The microscopic changes in lung were considered indicative of a persistent inflammatory reaction or persistent toxic effect on alveolar cells. Taking into account that trientine has irritating properties, it was estimated that the observed chronic interstitial pneumonitis was explained by a cytotoxic effect of trientine upon accumulation into bronchiolar epithelial cells and alveolar pneumocytes. These findings were not reversible. The rat NOAEL was considered 50 mg/kg/day for females, a NOAEL was not established for males. Dogs receiving oral doses of trientine up to 300 mg/kg/day, showed neurological and/or musculo-skeletal clinical symptoms (abnormal gait, ataxia, weak limbs, body tremors) in repeat-dose toxicity studies, attributed to the copper-depleting activity of trientine. The NOAEL was established at 50 mg/kg/day resulting in safety margins of about 4 in males and 17 in females, towards human therapeutic exposures.

Genotoxicity

Overall, trientine has shown positive effects in in vitro genotoxicity studies, including the Ames test and genotoxicity tests in mammalian cells. In vivo, trientine was however negative in the mouse micronucleus test.

Reproductive and developmental toxicity

When rodents were fed throughout pregnancy a diet containing trientine, the frequency of resorptions and the frequency of abnormal fetuses at term showed a dose-related increase. These effects are possibly due to trientine induced-copper and zinc deficiency.

Local tolerance

In silico data predict that trientine displays irritating and sensitising properties. Positive results for sensitization potential in Guinea pig maximization tests were reported.