Agalsidase alfa
Adverse Effects, Treatment, and Precautions
IgG antibodies to agalsidase alfa and beta develop in the majority of patients, who are consequently at increased risk of hypersensitivity reactions. Infusion reactions have been reported in about 14% of patients given agalsidase alfa, and in about 50% of patients treated with agalsidase beta. The frequency of the onset of these reactions decreases with continued use, with the majority of reports occurring during the first 6 months after the start of treatment, although onset after 1 year has also been reported. Symptoms generally start during, or within 1 hour of, infusion. The most common symptoms have included chills, dyspnoea, facial flushing, headache, nausea, fever, and fatigue. The infusion may be interrupted for about 5 to 10 minutes and restarted once symptoms have subsided. Pre-treatment with oral antihistamines, paracetamol, ibuprofen, and/or corticosteroids 1 to 24 hours before infusion has been used to prevent subsequent reactions. Patients with compromised cardiac function should be monitored closely since they may be predisposed to a higher risk of severe complications arising from infusion reactions.
Interactions
Agalsidase alfa or beta should not be used with amiodarone, chloroquine, monobenzone, or gentamicin, which all have the potential to inhibit intracellular ?-galactosidase activity.
Pharmacokinetics
The pharmacokinetic properties of agalsidase alfa appear to be unaffected by dose; the elimination half-life from blood following a single dose has been reported to be about 100 minutes. The pharmacokinetics of agalsidase beta indicate a saturated clearance; the elimination half-life following a single dose has been reported to range from 45 to 100 minutes.
Uses and Administration
Alpha galactosidase A is an endogenous enzyme that hydrolyses terminal ?-d-galactose residues in oligosaccharides and galactolipids into more easily digestible mono- and disaccharides. A form derived from a fungal source is used to prevent intestinal gas.
Agalsidase alfa and beta are recombinant forms of alpha galactosidase A used for the long-term enzyme replacement therapy of Fabry disease.
Agalsidase alfa is given by intravenous infusion in a dose of 200 micrograms/kg over 40 minutes, repeated every alternate week.
Agalsidase beta is given by intravenous infusion in a dose of 1 mg/kg at an initial rate of no more than 250 micrograms/minute; the rate may be gradually increased (by 5 to 8 micrograms/minute in each subsequent infusion) once tolerance has been established. The dose should be repeated every alternate week.
Fabry disease.
Fabry disease (Anderson-Fabry disease) is a rare X-linked recessive lysosomal storage disorder. It predominantly affects males, although female carriers may sometimes have clinical manifestations. It is characterised by a deficiency of the enzyme alpha galactosidase A resulting in the intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids, especially in vascular endothelium and smooth muscle. Symptoms include severe neuropathies, fevers, skin blemishes (angiokeratomas), corneal and lenticular opacities, and gastrointestinal disturbances. Cardiac, cerebrovascular, and renal deterioration is progressive placing patients at increased risk for early-onset myocardial infarction, stroke, and renal failure.
Symptomatic treatment was the only option until the development of enzyme replacement therapy with agalsidase alfa and beta. Results from controlled studies show this form of therapy to be effective in clearing deposits from the kidneys, heart, and skin as well as improving peripheral neuropathy. An open-label extension study of agalsidase beta in the 58 patients formerly studied in a 20-week controlled phase III study, and an analysis of data for agalsidase alfa held in an open-label observational outcomes database confirmed the continued safety and efficacy of enzyme replacement therapy after 12 to 30 months of treatment. However, long-term studies are necessary to evaluate the true potential. Although most studies have been in adults, and agalsidase alfa and beta are only licensed for use from 18 and 16 years of age respectively, enzyme replacement therapy is under evaluation in children; expert opinion generally recommends that treatment be begun as soon as clinical signs and symptoms are observed. Gene therapy is also under investigation.