Miglustat

Miglustat is a prescription drug used in the treatment of type 1 Gaucher disease, which is a hereditary disorder characterized by the accumulation of a protein called glucosylceramide. It is used in patients who cannot receive enzyme replacement therapy (Cerezyme).

Miglustat is sold under the brand name Zavesca by Galen Limited and Actelion Pharmaceuticals US Inc. It was approved by the Food and Drug Administration in 2002 and in the United Kingdom in 2003.

Diagram of a macrophage cell. These cells are involved in the disease process of Gaucher disease. Source:Wikimedia Commons.

Uses

Miglustat is used for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not an option (e.g., because of an allergy, hypersensitivity, or poor blood supply).

How Miglustat is Taken

Miglustat is available in 100 mg capsules that are taken three times a day by mouth. Sometimes the dose needs to be reduced to once or twice a day because of side effects, such as diarrhea or tremor, or in patients with kidney impairment.

How Miglustat Works

Type 1 Gaucher disease is caused by a deficiency in the levels of an enzyme called glucocerebrosidase. This enzyme degrades a protein called glucosylceramide. The failure to degrade glucosylceramide results in excessive storage of the protein within macrophages, which are cells of the immune system. Macrophages containing stored glucosylceramide are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Consequences of this accumulation include blood disorders (e.g., severe anemia), enlarged spleen and liver, and skeletal complications (e.g., bone weakening and loss).

Miglustat inhibits an enzyme called glucosylceramide synthase. This reduces the formation of compounds that react with the deficient enzyme seen in Gaucher disease. Consequently, the little amount of glucocerebrosidase in Gaucher disease is now available to metabolize glucosylceramide and prevent its buildup in macrophages.

How the Body Affects Miglustat

The levels of miglustat reach a peak in the blood two to three hours after a dose. The half-life of miglustat, or time necessary for the concentration of the drug in the blood to be reduced by half, is approximately six to seven hours. Miglustat is not metabolized. Instead, it is largely excreted unchanged in the urine. Kidney impairment reduces excretion, and this is why patients with kidney disease may need lower doses.

Side Effects

Below are some rare but serious side effects of miglustat:

• nerve problems such as numbness, tingling, and shaking of the hands
• allergic reactions including difficulty breathing and closing of the throat swelling of the lips, tongue, or face
• hives

Less serious side effects are more common:

• diarrhea
• decreased appetite or weight loss
• gas or abdominal pain
• constipation
• muscle cramps or weakness
• headache
• dizziness
• vision problems

Risks and Precautions

Males may need to use contraception when receiving miglustat. Studies in male rats have shown that miglustat reduces fertility by adversely affecting sperm production and motility.

Studies in laboratory animals have shown that miglustat can harm the fetus. Consequently, miglustat is no used in women who are pregnant or who are planning a pregnancy.

Drug Interactions

No drug interactions have been reported with miglustat.

Alternatives

Miglustat is the alternative treatment to enzyme replacement therapy (Cerezyme) in type 1 Gaucher patients.

Clinical Trials

The effectiveness of miglustat in type 1 Gaucher disease has been investigated in three studies with the traditional treatment of enzyme replacement (Cerezyme). A total of 80 patients were exposed to miglustat during all three studies.

Treatment with miglustat alone at a starting dose of 100 mg three times daily (dosage range 100 mg once daily to 200 mg three times daily) in adult type 1 Gaucher disease patients who either 1) never had treatment or who 2) had not taken enzyme replacement therapy in the previous 6 months resulted in the following:

• reduced liver and spleen volume after 12 months of treatment, and
• elevated platelet counts and hemoglobin concentration after 24 months of treatment.

In adult type I Gaucher disease patients who had been treated with enzyme replacement therapy for at least two years prior, switching to miglustat as the only treatment reduced platelet counts after discontinuation of enzyme replacement therapy. Platelet counts also declined after discontinuation of enzyme replacement therapy in patients treated with combination therapy.^[1]

An analysis of three clinical trials demonstrated that miglustat improves some of the skeletal complications of Gaucher disease.^[2] After two years, 83% of patients who took miglustat alone had no bone pain. Further, bone mineral density, which is a measure of bone strength, increased while taking miglustat. This suggests that the drug had a positive effect on bone strength.

References

1. ↑ Medical Information Department, Actelion Pharmaceuticals US, Inc.
2. ↑ Pastores GM, Elstein D, Hrebícek M, Zimran A. Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies. Clin Ther. 2007 Aug;29(8):1645-54. Abstract.

External Links

Zavesca.com

FDA: Zavesca

Rx List: Zavesca

Actelion Pharmaceuticals: Misglutat (Zavesca)