Imiglucerase

(BAN, USAN, rINN)
Synonyms: Imiglucerasa; Imiglucérase; Imiglucerasum; Imiglukeraasi; Imiglukeras; Imigluseraz; Recombinant Macrophage-targeted cocerebrosidase; r-GCR.
Cyrillic synonym: Имиглюцераза.

💊 Chemical information

CAS — 154248-97-2.
ATC — A16AB02.
ATC Vet — QA16AB02.

Description.

Imiglucerase is a recombinant human-derived βglucocerebrosidase. It is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites

💊 Adverse Effects and Precautions

Fever, chills, pruritus, flushing, and gastrointestinal symptoms, including cramps, diarrhoea, nausea, and vomiting have been reported after use of alglucerase or imiglucerase. Some of these may be hypersensitivity reactions; other hypersensitivity reactions, including urticaria and angioedema, respiratory symptoms, and hypotension have also occurred. Anaphylactoid reactions have occurred rarely with imiglucerase. Caution is required in patients who have exhibited signs of hypersensitivity; reduction of the rate of infusion, and pretreatment with antihistamines and/or corticosteroids may permit further treatment. Antibodies have developed in about 15% of patients receiving a glucocerebrosidase enzyme during the first year of therapy. Patients who develop antibodies are at increased risk of hypersensitivity reactions and periodic assessment for antibody formation is recommended. Pain and irritation at the injection site may occur. Other adverse effects reported include fatigue, dizziness, headache, backache, peripheral oedema, mouth ulcers, and disturbances in sense of smell. Alglucerase is prepared from human placentas and its infusion therefore carries a risk of transmission of infections although this is minimised by the manufacturing process. Chorionic gonadotrophin, a naturally occurring hormone in human placentas, has been detected in alglucerase. The presence of this hormone may produce early virilisation in young boys if sufficient is given, and has the potential to produce false positive results in pregnancy tests that rely on the detection of this hormone. Alglucerase should be used with caution, if at all, in patients with androgensensitive malignancies.
1. Starzyk K, et al. The long-term international safety experience of imiglucerase therapy for Gaucher disease. Mol Genet Metab 2007; 90: 157–63.

Effects on the lungs.

Pulmonary hypertension developed in 2 patients with Gaucher disease after starting treatment with alglucerase.1 Neither patient had evidence of parenchymal lung infiltration with Gaucher cells.
1. Dawson A, et al. Pulmonary hypertension developing after alglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med 1996; 125: 901–4.

💊 Pharmacokinetics

After intravenous infusion, plasma enzymatic activities of alglucerase and imiglucerase decline rapidly from steady state, with an elimination half-life of between 3.6 and 10.4 minutes.

💊 Uses and Administration

The enzyme β-glucocerebrosidase is given as imiglucerase (or occasionally alglucerase) for long-term enzyme replacement therapy to patients with symptomatic Gaucher disease (see below). The oligosaccharide chains of the enzyme are modified to terminate with mannose residues to ensure uptake into macrophages. Imiglucerase is given by intravenous infusion over 1 to 2 hours for the treatment of type 1 or type 3

Gaucher disease.

Alternatively, the dose may be infused at a rate not exceeding 1 unit/kg per minute. The dosage depends on the severity of symptoms, and initial doses can vary from 2.5 units/kg three times weekly to 60 units/kg once every two weeks. Further increases or decreases in doses are made according to individual response. Once the patient’s condition is stabilised, monitoring and dosage adjustment up or down is carried out at usual intervals of 6 to 12 months. In the UK, the BNFC notes that higher doses of 120 units/kg infused over 1 to 2 hours are given once every 2 weeks for type 3

Gaucher disease.

Alglucerase has been given by intravenous infusion in similar doses with monitoring and dosage adjustment at intervals of 3 to 6 months in stabilised patients with type 1

Gaucher disease.Gaucher disease.

Gaucher disease1-4 (glucocerebrosidosis) is a rare, autosomal recessive disorder, although it is the commonest lysosomal storage disorder. It is caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase (acid β-glucosidase, ceramide glucosidase, β-D-glucosyl-N-acylsphingosine glucohydrolase, or glucosylceramidase) which catalyses the hydrolysis of glucocerebroside, a lipid component of cell membranes, to glucose and ceramide. Deficiency of β-glucocerebrosidase results in accumulation of glucocerebroside in the lysosomes of reticuloendothelial cells, particularly macrophages. Gaucher disease is classified into three main forms based on clinical signs and symptoms. Hepatosplenomegaly occurs in all forms. Type 1 Gaucher disease (chronic adult non-neurono pathic disease) accounts for 90% or more of cases and occurs especially in Ashkenazi Jews. More than half of all patients with type 1 disease are diagnosed before the age of 10 years.5 The disease follows a chronic course of variable severity and onset, with hepatosplenomegaly and blood and bone disorders being the main features; there is no neurological involvement. In type 2 Gaucher disease (acute infantile neuronopathic disease), neurological involvement predominates. Patients show developmental delay by the age of 6 months, suffer seizures, pulmonary infections, and usually die in early childhood. Type 3 Gaucher disease is a subacute neuronopathic form and is slowly progressive.4 There are 3 subtypes varying in severity and prognosis: in type 3a, there is slow progressive neurological deterioration with death usually occurring during childhood; in type 3b (Norrbotten disease) there is slow cognitive deterioration and patients may survive to adulthood; type 3c typically affects patients of Palestinian, Arab, or Japanese descent, with possible survival to the teenage years. Treatment of Gaucher disease was previously limited to symptomatic management until the development of enzyme replacement therapy with β-glucocerebrosidase. Due to the rarity of Gaucher disease, early clinical studies were limited mainly to small case series of patients with type 1 disease. Use of alglucerase or imiglucerase has been shown to reverse hepatosplenomegaly and the haematological abnormalities;6,7 effects may be seen within a few months, although in many the response is poor during the first 6 to 9 months and then improves rapidly.2Return to normal haemoglobin values within 6 to 12 months has been reported, as has reduction in liver size by 20 to 30% within 2 years and 30 to 40% by 5 years; a 50% reduction in spleen size also occurred.8 Bone symptoms respond more slowly. Decreases in bone pain during the first year of treatment have been reported although there was no radiological improvement.7 Existing bone manifestations are slow to respond or refractory to enzyme replacement therapy, but alendronate has been shown to be of benefit as adjunctive therapy for osteopenia in 36 adults with negative lumbar bone mineral density scores who had been receiving glucocerebrosidase for at least 2 years.9 Normalised growth velocity has been reported in children10 and radiographical assessments have shown improvements in bone density and mineralisation.11 There is evidence that long-term enzyme replacement therapy for up to 5 years completely or partially ameliorates anaemia, thrombocytopenia, organomegaly, and bone pain in patients with type 1 Gaucher disease, as well as preventing further deterioration.8 However, successful symptom control is dependent on the degree of damage that has already occurred, and early initiation of therapy is recommended for a more favourable prognosis. Enzyme replacement therapy in Gaucher disease is lifelong and relapses occur with prolonged interruptions to therapy.5,12 Alglucerase has also been tried in rare cases of Gaucher disease affecting the heart13 or the eye.14 It is not yet known whether enzyme replacement therapy is able to prevent the development of symptoms in asymptomatic patients. The efficacy of enzyme replacement therapy in managing neurological symptoms in patients with type 2 or type 3 disease15 remains to be established. Most of the patients with type 3 Gaucher disease in a small study16 did not deteriorate neurologically when treated with doses that reversed almost all the systemic manifestations. However, it was pointed out that the amount of enzyme that crosses the blood-brain barrier is unlikely to be significant, and other forms of treatment specifically for neuronopathic Gaucher disease need to be developed. For those patients with type 1 Gaucher disease in whom enzyme replacement therapy may be unsuitable, miglustat may be used. It reduces the synthesis of glucocerebroside by inhibiting glucosyltransferase, one of the early enzymes in the sphingolipid biosynthetic pathway. However, the balance of benefits versus adverse affects with miglustat is less favourable than with imiglucerase, which remains the standard treatment where possible; the two drugs should not be used together.17 Possible future therapies under investigation for Gaucher disease include oral therapy with the pharmacological chaperone isofagomine, and gene therapy. Other modified forms of β-glucocerebrosidase are also under investigation to improve uptake into the affected macrophages.
1. NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease: current issues in diagnosis and treatment. JAMA 1996; 275: 548–53
2. Morales LE. Gaucher’s disease: a review. Ann Pharmacother 1996; 30: 381–8
3. Elstein D, et al. Gaucher’s disease. Lancet 2001; 358: 324–7
4. Grabowski GA. Gaucher disease: lessons from a decade of therapy. J Pediatr 2004; 144 (suppl): S15–S19
5. Charrow J, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr 2004; 144: 112–20
6. Grabowski GA, et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 1995; 122: 33–9
7. Pastores GM, et al. Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood 1993; 82: 408–16
8. Weinreb NJ, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 2002; 113: 112–19
9. Wenstrup RJ, et al. Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy. Blood 2004; 104: 1253–7
10. Kaplan P, et al. Acceleration of retarded growth in children with Gaucher disease after treatment with alglucerase. J Pediatr 1996; 129: 149–53
11. Rosenthal DI, et al. Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics 1995; 96: 629–37
12. Drelichman G, et al. Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease. J Pediatr 2007; 151: 197–201
13. Spada M, et al. Cardiac response to enzyme-replacement therapy in Gaucher’s disease. N Engl J Med 1998; 339: 1165–6
14. vom Dahl S, et al. Loss of vision in Gaucher’s disease and its reversal by enzyme-replacement therapy. N Engl J Med 1998; 338: 1471–2
15. Bembi B, et al. Enzyme replacement treatment in type 1 and type 3 Gaucher’s disease. Lancet 1994; 344: 1679–82
16. Altarescu G, et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher’s disease. J Pediatr 2001; 138: 539–47
17. Weinreb NJ, et al. Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol 2005; 80: 223–9.

💊 Preparations

Proprietary Preparations

Austral.: Cerezyme; Austria: Cerezyme; Belg.: Cerezyme; Canad.: Cerezyme; Cz.: Cerezyme; Denm.: Cerezyme; Fin.: Cerezyme; Ger.: Cerezyme; Gr.: Cerezyme; Hong Kong: Cerezyme; Israel: Ceredase†; Cerezyme; Ital.: Cerezyme; Jpn: Ceredase†; Cerezyme; Neth.: Cerezyme; Norw.: Cerezyme; NZ: Cerezyme; Pol.: Cerezyme; Port.: Cerezyme; S.Afr.: Cerezyme; Spain: Cerezyme; Swed.: Cerezyme; Switz.: Cerezyme; UK: Cerezyme; USA: Ceredase; Cerezyme.
Published November 23, 2018.