Eliglustat

Eliglustat (brand name Cerdelga) is an oral substrate reduction therapy approved for long-term treatment of adults with Gaucher disease type 1. It works by inhibiting glucosylceramide synthase, the enzyme responsible for the first step in glycosphingolipid synthesis.

Eliglustat is indicated to reduce spleen and liver volume, improve hematologic parameters, and slow disease progression in Gaucher disease type 1 patients. By lowering the production of glucosylceramide, it helps to prevent its accumulation in macrophages.

The mechanism of action is competitive inhibition of glucosylceramide synthase in the Golgi apparatus of cells. This decreases substrate accumulation in the lysosomes of macrophages, thereby mitigating organ enlargement and bone complications associated with Gaucher disease.

The primary gene affecting eliglustat metabolism is CYP2D6. CYP2D6 is a liver enzyme in the cytochrome P450 family that converts eliglustat into inactive metabolites. Genetic variants in CYP2D6 can categorize individuals as ultrarapid, normal, intermediate, or poor metabolizers based on enzyme activity.

Genetic alterations in CYP2D6 change how quickly eliglustat is broken down and cleared from the body. For example, poor metabolizers have lower enzyme activity and higher drug exposure, whereas ultrarapid metabolizers may clear the drug too quickly to maintain therapeutic levels. Understanding your CYP2D6 status helps guide dosing to achieve safe and effective drug concentrations.

CYP2D6 phenotype groups influence eliglustat plasma concentrations, efficacy, and risk of adverse events such as QT prolongation. Ultrarapid metabolizers clear the drug faster, which may lead to subtherapeutic levels and reduced benefit. Poor metabolizers have elevated exposure, which increases the risk of toxicity if dosing is not adjusted.

Ultrarapid Metabolizer

• Effect on drug levels: Very low plasma concentration due to rapid clearance
• Clinical consequence: Reduced efficacy; may not achieve therapeutic benefit
• Side effects: Minimal drug-related adverse events but risk of disease progression if under-dosed

Normal Metabolizer

• Effect on drug levels: Expected plasma concentration with standard dosing
• Clinical consequence: Optimal efficacy and safety profile
• Side effects: Headache, fatigue, abdominal pain; generally mild and infrequent

Intermediate Metabolizer

• Effect on drug levels: Moderately increased plasma exposure
• Clinical consequence: Higher risk of QT prolongation and other dose-related adverse effects
• Side effects: Dose-related nausea, diarrhea; monitor ECG and adjust dose if needed

Poor Metabolizer

• Effect on drug levels: Significantly elevated plasma concentration
• Clinical consequence: High risk of QT prolongation and toxicity without dose adjustment
• Side effects: Potential serious cardiac effects; headaches and gastrointestinal symptoms may be more pronounced

Indeterminate/Not Available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

CYP2D6 Dosing Guideline

Examples of alternative therapies include enzyme replacement treatments such as imiglucerase (Cerezyme) or velaglucerase alfa (Vpriv), and substrate reduction with miglustat. These alternatives are drawn from treatment guidelines and should not be taken as personalized medical advice.

• FDA – Table of Pharmacogenetic Associations