Introduction

Wilson’s disease (hepatolenticular degeneration) is an autosomal inherited metabolic defect resulting in an inability to maintain a near-zero balance of copper. Excess copper accumulates possibly because the liver lacks the mechanism to excrete free copper into the bile. Hepatocytes store excess copper but when their capacity is exceeded copper is released into the blood and is taken up into extrahepatic sites. This condition is treated with a low copper diet and the use of chelating agents that bind copper to facilitate its excretion from the body.

Clinical Summary

Forty-one patients (18 male and 23 female) between the ages of 6 and 54 with a diagnosis of Wilson’s disease and who were intolerant of d-penicillamine were treated in two separate studies with trientine HCl. The dosage varied from 450 to 2,400 mg per day. The average dosage required to achieve an optimal clinical response varied between 1,000 mg and 2,000 mg per day. The mean duration of trientine HCl therapy was 48.7 months (range 2 to 164 months). Thirty-four of the 41 patients improved, 4 had no change in clinical global response, 2 were lost to follow-up and one showed deterioration in clinical condition. One of the patients who improved while on therapy with trientine HCl experienced a recurrence of the symptoms of systemic lupus erythematosus which had appeared originally during therapy with penicillamine. Therapy with trientine HCl was discontinued. No other adverse reactions, except iron deficiency, were noted among any of these 41 patients.

One investigator treated 13 patients with trientine HCl following their development of intolerance to d-penicillamine. Retrospectively, he compared these patients to an additional group of 12 patients with Wilson’s disease who were both tolerant of and controlled with d-penicillamine therapy, but who failed to continue any copper chelation therapy. The mean age at onset of disease of the latter group was 12 years as compared to 21 years for the former group. The trientine HCl group received d-penicillamine for an average of 4 years as compared to an average of 10 years for the non-treated group.

Various laboratory parameters showed changes in favor of the patients treated with trientine HCl. Free and total serum copper, SGOT and serum bilirubin all showed mean increases over baseline in the untreated group which were significantly larger than with the patients treated with trientine HCl. In the 13 patients treated with trientine HCl, previous symptoms and signs relating to d-penicillamine intolerance disappeared in 8 patients, improved in 4 patients, and remained unchanged in one patient. The neurological status in the trientine hydrochloride group was unchanged or improved over baseline, whereas in the untreated group, 6 patients remained unchanged and 6 worsened. Kayser-Fleischer rings improved significantly during trientine HCl treatment.

The clinical outcome of the two groups also differed markedly. Of the 13 patients on therapy with trientine HCl (mean duration of therapy 4.1 years; range 1 to 13 years), all were alive at the data cutoff date, and in the non-treated group (mean years with no therapy 2.7 years; range 3 months to 9 years), 9 of the 12 died of hepatic disease.

Chelating Properties

Preclinical Studies

Studies in animals have shown that trientine HCl has cupriuretic activities in both normal and copper-loaded rats. In general, the effects of trientine HCl on urinary copper excretion are similar to those of equimolar doses of penicillamine, although in one study they were significantly smaller.

Human Studies

Renal clearance studies were carried out with penicillamine and trientine HCl on separate occasions in selected patients treated with penicillamine for at least one year. Six-hour excretion rates of copper were determined off treatment and after a single dose of 500 mg of penicillamine or 1.2 g of trientine HCl. The mean urinary excretion rates of copper were as follows:

In patients not previously treated with chelating agents, a similar comparison was made:

These results demonstrate that trientine HCl is effective as a cupriuretic agent in patients with Wilson’s disease although on a molar basis it appears to be less potent or less effective than penicillamine. Evidence from a radio-labelled copper study indicates that the different cupriuretic effect between these two drugs could be due to a difference in selectivity of the drugs for different copper pools within the body.