Brands, Medical Use, Clinical Data
Drug Category
- Anti-HIV Agents
- Enzyme Inhibitors
Dosage Forms
- Capsules (100-mg) for oral administration
Brands / Synonyms
Miglustat, Hydrochloride; Zavesca; Zavesca
Indications
For the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access).
Pharmacology
Miglustat is an N-alkylated imino sugar, a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids.
Mechanism of Action
Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count.
Absorption
Mean oral bioavailability is 97%.
Toxicity
Miglustat has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.
Biotrnasformation / Drug Metabolism
There is no evidence that miglustat is metabolized in humans.
Contraindications
ZAVESCA® is contraindicated in patients who have demonstrated hypersensitivity to the active
substance or any of the excipients.
Pregnancy Category X.
Miglustat may cause fetal harm when administered to a pregnant woman. In female rats given miglustat
by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day
17 (organogenesis), decreased live births including complete litter loss and decreased fetal weight was observed in
the mid and high-dose groups (systemic exposures ³2 times the human therapeutic
systemic exposure based on body surface area comparison). In pregnant rats given miglustat by oral gavage at doses of
20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20), dystocia and delayed parturition
were observed in the mid- and high-dose groups (systemic exposures ³2 times the human
therapeutic systemic exposure, based on body surface area comparison), in addition decreased live births and pup body
weights were observed at >20 mg/kg/day (systemic exposures less than the human
therapeutic systemic exposure, based on body surface area comparison).
In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation
days 6-18 (organogenesis), maternal death and decreased body weight gain were observed at 15 mg/kg/day (systemic
exposures less than the human therapeutic systemic exposure, based on body surface area comparisons).
ZAVESCA® is contraindicated in women who are or may become pregnant. If this drug is administered
to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus.
Drug Interactions
While co-administration of ZAVESCA® appeared to increase the clearance of Cerezyme by 70%, these
results are not conclusive because of the small number of subjects studied and because patients took variable doses
of Cerezyme. Combination therapy with Cerezyme® (imiglucerase) and ZAVESCA® is not indicated.
|