Single Daily Dosage of Trientine for Maintenance Treatment for Wilson Disease

Wilson disease is a genetic disorder of copper metabolism inherited in an autosomal recessive fashion that afflicts ~1/30,000 individuals. Treatment for these individuals consists of medical therapy, which is life-long, or liver transplantation. Medical therapy utilizes chelating agents, penicillamine and trientine, or zinc, each given in multiple daily dosages (1). It is estimated that ~10-50% of individuals have some period of non-adherence to their therapy during their life-time. The consequences of non-adherence include liver injury, liver failure, neurological impairment and death. Some non-adherent individuals can be rescued by reinstitution of medical therapy, while others require liver transplantation (1-4). In addition to the human suffering engendered by the advance in an individuals disease suffered from non-adherence, the physical or mental disability suffered or the need for liver transplantation adds greatly to their cost of life-time care. Simplifying the current treatment regimen for long-term maintenance therapy for Wilson disease should improve patient adherence. This will translate into a positive long-term benefit for patients, their caregivers and supports, and for society as a whole.

Current maintenance therapy for Wilson disease includes the chelating agents penicillamine and trientine, or zinc. Multiple daily dosages (three or four) are recommended from early studies on these medications, by the manufacturer and by treating physicians (1,5-8). As noted above, patient adherence to treatment, and in particular to multiple daily dosages is often incomplete. There has been an increase in the treatment of other common disorders with medication that can be administered as a single daily dosage. As an example, some anti-hypertensives and antidepressants are available in extended release formulations, making a single daily dosage possible. None of the currently available agents for the treatment of Wilson disease has a comparable formulation. Furthermore, even if an extended release oral formulation were available, it is not certain that it would be effective. In an extended release formulation, the site of absorption of the medication may not be sustained adequately, and binding to ingested food may interfere with its function.

The choice of trientine as the single agent for use for study comes from personal experience of the Principal Investigator with its' use in the clinical setting and in a clinical trial (1, 9). This drug has an excellent safety profile and is effective in removing copper from the body when given apart from meals (1,4,10). Previous studies have shown the effectiveness of copper removal by administration in multiple daily dosages (10,11). The amount of copper excreted in the urine of patients on a daily basis is dosage dependent, and is also dependent on the phase of treatment. In the initial treatment period, there is a larger efflux of copper in the urine of patients treated with chelation agents, and with time this amount decreases. For example, patients maintained on d-penicillamine initially may excrete over one milligram of copper in a 24 hour period, but over time will excrete ~250 mcg copper per day. Similarly, patients maintained on trientine as a single therapy may excrete slightly less but comparable amounts of copper (11). In the trials of trientine for neurological disease, the amount of free serum copper and urine copper was stable by the end of the initial 8 week period in most patients (9). Once equilibrium is achieved with respect to copper balance and liver function is stabilized, maintenance therapy is geared towards a smaller net negative removal of copper on a daily basis. Therefore, adequate copper removal should be possible to achieve with an appropriate dosage of trientine given once daily since there is known to be a dose response between trientine and copper excretion.

Supportive evidence suggesting that the single daily dosage proposed in this study will be effective therapy was recently obtained by review of three individual case studies. These three patients, two followed by the principal investigator (MLS) and the third known to him but followed locally, reported taking their trientine as a single daily dosage. Two of the patients had presented with neurological Wilson disease, while the third was a presymptomatic patient identified by family screening; all were years out from their initial treatment. Two of the three changed their regimens to once a day treatment on their own without the advice of their physician due to difficulty taking multiple dosages during their working hours or interference with taking other medications, and the third did so at the advice of another physician. Each of these patients had used single dose therapy for years (range 2-15). Laboratory data for these individuals demonstrated normal liver function and good copper control, and examinations showed them to be clinically stable. All three had previously been treated with d- Penicillamine and then trientine in multiple daily dosages.

Experimental Design & Methods: