Eliglustat
Regulatory sources consulted
Approved indications
- Long-term treatment of adults with type 1 Gaucher disease who are CYP2D6 extensive, intermediate, or poor metabolisers identified by an FDA-cleared test.
- Spain: treatment of paediatric patients aged 6 to under 18 years with type 1 Gaucher disease, weighing at least 15 kg, stable on enzyme replacement therapy and CYP2D6 poor, intermediate or extensive metabolisers.
Contraindications
Absolute
- Extensive metabolisers: contraindicated with a strong or moderate CYP2D6 inhibitor together with a strong or moderate CYP3A inhibitor; with moderate or severe hepatic impairment; or with mild hepatic impairment plus a strong or moderate CYP2D6 inhibitor.
- Intermediate metabolisers: contraindicated with a strong or moderate CYP2D6 inhibitor together with a strong or moderate CYP3A inhibitor; with a strong CYP3A inhibitor; or with any degree of hepatic impairment.
- Poor metabolisers: contraindicated with a strong CYP3A inhibitor or with any degree of hepatic impairment.
- Hypersensitivity to eliglustat or any excipient.
Clinical warnings
- Major warning · Substantially elevated plasma concentrations may prolong PR, QTc, or QRS intervals and increase arrhythmia risk; always review CYP2D6 phenotype, renal and hepatic function, and concomitant medicines. — DailyMed CERDELGA setid 819f828a-b888-4e46-83fc-94d774a28a83
- Major warning · Avoid in pre-existing cardiac disease, long-QT syndrome, and with class IA or III antiarrhythmics. — DailyMed CERDELGA setid 819f828a-b888-4e46-83fc-94d774a28a83
Drug interactions
- HighCYP2D6 inhibitors
Mechanism: They increase eliglustat exposure and the risk of PR, QTc, or QRS prolongation and arrhythmias.
Recommendation: Apply the phenotype matrix: in extensive metabolisers, reduce to 84 mg once daily with strong or moderate inhibitors and continue twice daily with weak inhibitors; in intermediate metabolisers, continue 84 mg once daily with strong or moderate inhibitors; in poor metabolisers they do not alter the regimen. Also review any CYP3A inhibitor and hepatic function.
DailyMed setid:819f828a-b888-4e46-83fc-94d774a28a83
- HighCYP3A inhibitors
Mechanism: They increase eliglustat exposure and the risk of concentration-dependent arrhythmias.
Recommendation: In extensive metabolisers without hepatic impairment, reduce to 84 mg once daily with strong or moderate inhibitors and continue twice daily with weak inhibitors. In intermediate or poor metabolisers, strong inhibitors are contraindicated and moderate or weak inhibitors should be avoided. Apply the additional restrictions in hepatic impairment.
DailyMed setid:819f828a-b888-4e46-83fc-94d774a28a83
- HighStrong CYP3A inducers
Mechanism: They reduce eliglustat concentrations and may decrease efficacy.
Recommendation: Avoid concomitant administration in all CYP2D6 phenotypes.
DailyMed setid:819f828a-b888-4e46-83fc-94d774a28a83
- ModerateDigoxin and other P-gp or CYP2D6 substrates
Mechanism: Eliglustat may increase concentrations of P-gp or CYP2D6 substrates and their toxicity.
Recommendation: Measure digoxin before initiation, reduce its dose by 30%, and continue monitoring. For other substrates, monitor concentrations when indicated or consider dose reduction.
DailyMed setid:819f828a-b888-4e46-83fc-94d774a28a83
Adverse events
Common (≥1%)
Fatigue · Headache · Nausea · Diarrhoea · Back pain · Pain in extremities · Upper abdominal pain
Rare but serious
Cardiac arrhythmia
Pregnancy and lactation
As a precaution, eliglustat use during pregnancy should preferably be avoided. No human-milk data are available; eliglustat was present in animal milk.
Recent literature (PubMed)
This focused review concentrates on eight topics of high importance for Gaucher disease (GD) clinicians and researchers: 1) The consideration of GD as distinct types rather than a spectrum. A review of the literature clearly supports the view that there are distinct types of GD. Type 1 is characterized by the absence of primary neuronopathic involvement, while types 2 and 3 are characterized by progressive primary neuronopathic disease. 2) Neurologic and neuronopathic manifestations. A growing body of evidence indicates that the peripheral nervous system may be involved in GD type 1 and that there may also be signs and symptoms of central nervous system (CNS) disease in this group. However, GD type 1 is characterized by the absence of primary neuronopathic disease, whereas GD types 2 and 3 are characterized by progressive, albeit variable, primary neuronopathic disease. Abnormalities in saccadic eye movements have been suggested as being diagnostic for neuronopathic GD, but they may also occur in GD type 1 and in other inflammatory diseases. 3) The importance of whole GBA1 sequencing. This approach is superior to exome sequencing because of potential effects of deep intronic variants on gene expression. It also has the capacity to detect variant alleles that might be missed with gene panels. 4) Monoclonal gammopathy of undetermined significance (MGUS). The risks of MGUS, multiple myeloma, and non-Hodgkin's lymphoma are elevated in patients with GD compared to the general population and strong evidence indicates that lyso-Gb1 stimulates the formation of monoclonal immunoglobulins (M-protein) in patients with GD and MGUS. 5) Pulmonary involvement in GD. Pulmonary complications can be identified through spirometry in up to 45 % of patients with GD type 1 and 55 % of those with GD type 3. Limited evidence exists that enzyme replacement therapy (ERT) reduces the severity of these complications in patients with GD type 1. 6) Gaucheromas. These may occur in patients with G
Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach. Eliglustat (brand name CERDELGA) is a glucosylceramide synthase inhibitor used in the treatment of Gaucher disease (GD). Eliglustat is indicated for the long-term treatment of adult individuals with Gaucher disease type 1 (GD1) who are CYP2D6 normal metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test (1). Gaucher disease is an autosomal recessive metabolic disorder characterized by accumulation of glucosylceramide (a sphingolipid also known as glucocerebroside) within lysosomes. This is caused by a malfunction of the enzyme acid beta-glucosidase, encoded by the gene GBA. Type 1 GD may present in childhood or adulthood with symptoms including bone disease, hepatosplenomegaly, thrombocytopenia, anemia and lung di