Cuprimine (penicillamine) is an oral medication belonging to the class of drugs called heavy metal chelators that was approved in 1956 to treat Wilson disease (WD),1 which is an inherited condition caused by mutations in the ATP7B gene that prevent copper excretion in the bile, resulting in its accumulation in several organs and tissues including the liver and brain.2

Treatment with penicillamine is lifelong and challenging due to the high frequency of early and late adverse effects. Because of these side effects, researchers are investigating new therapies with fewer side effects to replace penicillamine as the first line of treatment.3

How Penicillamine Works

Penicillamine was first identified as a breakdown product of penicillin and has a sulfhydryl group, which functions as the copper-chelating moiety. It works by binding to excess extracellular copper in the body, forming stable complexes that are later removed by the kidneys in the urine. Thus, penicillamine lowers copper concentration in the body by promoting its urinary excretion.3,4

Besides its chelation property, it has been suggested to reduce the cellular toxicity of copper to the hepatocytes by inducing metallothionein that combines with copper to form a non-toxic complex.4

Penicillamine can also induce the release of intracellular stores of metallothionein, an endogenous copper chelator, which can further lower copper toxicity.3,4 

Penicillamine molecule
Penicillamine, D-penicillamine C5H11NO2S molecule. It is chelating agent, an antirheumatic and allergen drug. Skeletal chemical formula. Credit: Getty Images

Pharmacokinetics

Penicillamine absorption is rapid but incomplete: only 40% to 70% is absorbed from the gastrointestinal tract. In addition, drug absorption is reduced by food, antacids, and iron. The plasma concentration of penicillamine reaches peak levels 1 to 3 hours after ingestion (approximately 1 to 2 mg/L after an oral dose of 250 mg). The drug appears in the plasma as free penicillamine, penicillamine disulfide, and penicillamine-cysteine disulfide. More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug also binds to erythrocytes and macrophages. After prolonged treatment is stopped, penicillamine is eliminated from the body slowly over a period of 4 to 6 days. A small fraction is metabolized in the liver to S-methyl-D-penicillamine, which is excreted by the kidneys, mainly as disulfides.3,5

Administration

It is important that penicillamine is given on an empty stomach, at least 1 hour before a meal or 2 hours after a meal, and at least 1 hour apart from any other drug, food, milk, antacid, zinc, or iron-containing preparation; food can inhibit its absorption by almost 50%. The intake of penicillamine on an empty stomach allows its maximum absorption and reduces the likelihood of its inactivation by metal binding in the gastrointestinal tract.3,5 

The tolerability of penicillamine may be enhanced by gradually increasing the dose, starting with a daily dose of 250 to 500 mg and increasing it by 250 mg/day every 4 to 7 days, up to a maximum dose of 1000 to 1500 mg/day (given over 2 to 4 doses). Increasing the dose gradually reduces the risk of adverse events and worsening of any neurologic symptoms. During maintenance, the daily dose can be reduced to 750 to 1000 mg (administered in 2 doses). Penicillamine can also be used in children at a dose of 20 mg/kg/day given over 2 to 3 doses.3,5

Read more about Wilson disease therapies

Diet

Doctors usually recommend that patients with WD consume a special low-copper diet that excludes copper-rich foods such as nuts, chocolate, shellfish, liver, mushrooms, molasses, broccoli, and cereals as well as dietary supplements enriched with copper. They may also recommend distilled or demineralized water instead of regular tap water.3 

Side Effects

Penicillamine is associated with numerous side effects, which cause treatment discontinuation in approximately 30% of patients. Side effects observed during the first 3 weeks of treatment, called early adverse events, include fever, generalized pruritus and rashes, lymphadenopathy, and proteinuria. Paradoxically, the risk of worsening neurologic symptoms increases during the first few weeks of treatment and is reported in up to 50% of patients with WD.6 Late adverse effects include progressive proteinuria; hair loss; gastric symptoms; hypogeusia; leukopenia, thrombocytopenia, or total aplasia due to bone marrow depression; and myasthenia- or lupus-like syndrome marked by hematuria and antinuclear antibody positivity. Chronic treatment with penicillamine may also cause a decrease in serum ceruloplasmin levels in patients with WD, which may be a sign of excessive copper depletion. This decrease is often associated with neutropenia, sideroblastic anemia, and hemosiderosis.3,5

Get full prescribing information about Cuprimine at MPR

References

  1. Walshe JM. Wilson’s disease; new oral therapy. Lancet. 1956;270(6906):25-26. doi:10.1016/s0140-6736(56)91859-1
  2. ATP7B gene: ATPase copper transporting beta. MedlinePlus. Updated February 1, 2007. Accessed September 29, 2022.
  3. Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases. 2022;10(14):4334-4347. doi:10.12998/wjcc.v10.i14.4334
  4. Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. doi:10.1002/hep.22261
  5. Cuprimine (penicillamine). Prescribing information. Bausch Health US, LLC; 2020. Accessed September 29, 2022.
  6. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol. 1987;44(5):490-493. doi:10.1001/archneur.1987.00520170020016

Reviewed by Hasan Avcu, MD, on 9/30/2022.

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