Eliglustat

Oral
Gaucher disease type 1

Pharmacogenomics:

Eliglustat is extensively metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites. The CYP2D6 phenotype status of the patient influences the efficacy and safety of eliglustat. Therefore, various guidelines recommend genotyping of CYP2D6 prior to eliglustat therapy to determine appropriate dosing.

CYP2D6 phenotypes are classified as ultrarapid metabolisers (UM), extensive metabolisers (EM), intermediate metabolisers (IM) and poor metabolisers (PM). The blood concentrations of eliglustat depend on the CYP2D6 metaboliser phenotype of the patient. Patients who are PM have 7-9-fold higher plasma concentrations of eliglustat as compared to normal metabolisers while ultrarapid metabolisers have the lowest systemic exposure. Patients who are CYP2D6 ultrarapid metabolisers may not have adequate levels of eliglustat to achieve a therapeutic effect, thus, eliglustat is contraindicated.

Dutch Pharmacogenetics Working Group (DPWG) Guideline as of November 2018

CYP2D6 Ultrarapid metabolisers:

This genetic variation increases the eliglustat conversion to inactive metabolites; thus, a normal dose may not be sufficient to achieve a therapeutic effect. Eliglustat use is contraindicated. Use an alternative drug if possible.

CYP2D6 Intermediate metabolisers:

This genetic variation reduces eliglustat conversion to inactive metabolites. In the absence of CYP2D6 and CYP3A inhibitors, however, this may not result in a clinically significant increase in side effects.

Co-administration with both a moderate (e.g. duloxetine) or strong (e.g. paroxetine) CYP2D6 inhibitor and a moderate (e.g. erythromycin) or strong (e.g. ketoconazole) CYP3A inhibitor: Contraindicated. Use an alternative.

Co-administration with a strong CYP2D6 inhibitor: Adjust the dose to 84 mg once daily.

Co-administration with a moderate CYP2D6 inhibitor: Consider a dose of 84 mg once daily. Monitor for side effects.

Co-administration with a strong CYP3A inhibitor: Use an alternative. If not possible, consider a dose of 84 mg once daily. Monitor for side effects.

Co-administration with a moderate CYP3A inhibitor: Use an alternative. If not possible, consider a dose of 84 mg once daily. Monitor for side effects.

Co-administration with a strong CYP3A inducer (e.g. rifampicin): Use an alternative.

CYP2D6 Poor metabolisers:

This genetic variation reduces the eliglustat conversion to inactive metabolites. This results in an increased risk of side effects (e.g. QT interval prolongation). Concomitant use with CYP3A inhibitors further increases the risk of adverse effects.

Co-administration with a strong CYP3A inhibitor: Use an alternative.

Co-administration with a moderate CYP3A inhibitor: Use an alternative.

Co-administration with a weak CYP3A inhibitor (e.g. amlodipine): Use an alternative for the weak CYP3A inhibitor. If not possible, adjust the dose to 84 mg once daily. Monitor for side effects.

Co-administration with a strong CYP3A inducer: Use an alternative.

CrCl (mL/min)	Dosage
≥15	CYP2D6 IMs and PMs: Contraindicated.
<15 (ESRD; with or without dialysis)	CYP2D6 EMs, IMs, and PMs: Contraindicated.

Mild (Child-Pugh class A): CYP2D6 EMs taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A4 inhibitor: 84 mg once daily. CYP2D6 EMs taking a strong or moderate CYP2D6 inhibitor; IMs; PMs: Contraindicated. Moderate to severe (Child-Pugh class B and C): EMs, IMs, and PMs: Contraindicated.

May be taken with or without food.

Cardiac disease (e.g. CHF, recent acute MI, bradycardia, ventricular arrhythmia, heart block), long QT syndrome. CYP2D6 ultrarapid or indeterminate metabolisers. CYP2D6 EMs taking a strong or moderate CYP2D6 inhibitor, IMs and PMs with mild hepatic impairment. CYP2D6 EMs, IMs and PMs with moderate to severe hepatic impairment. CYP2D6 IMs and PMs with mild to severe renal impairment. CYP2D6 EMs, IMs, and PMs with ESRD (with or without dialysis). CYP2D6 IMs or EMs taking a strong or moderate CYP2D6 inhibitor concurrently with a strong or moderate CYP3A inhibitor. CYP2D6 PMs taking weak to strong CYP3A inhibitor. Concurrent use of class IA (e.g. quinidine, procainamide) and class III (e.g. amiodarone, sotalol) antiarrhythmic drugs.

CYP2D6 EMs with mild hepatic impairment and are taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A4 inhibitor. Pregnancy and lactation. CYP2D6 EMs taking strong or moderate CYP2D6 inhibitor or CYP3A inhibitor and IM taking strong or moderate CYP2D6 inhibitor.

Cardiac disorders: Palpitations.
Gastrointestinal disorders: Upper abdominal pain, diarrhoea, nausea, constipation, GERD, flatulence, oropharyngeal pain, dyspepsia.
General disorders and admin site conditions: Fatigue.
Musculoskeletal and connective tissue disorders: Arthralgia, pain in extremities, back pain.
Nervous system disorders: Headache, migraine, dizziness.
Respiratory, thoracic and mediastinal disorders: Cough.
Skin and subcutaneous tissue disorders: Rash.

PO: C

Perform CYP2D6 genotyping prior to therapy. Monitor liver and kidney functions, ECG, and signs of adverse reactions.

Symptoms: Dizziness marked by disequilibrium, hypotension, bradycardia, nausea, vomiting. Management: Symptomatic and supportive treatment.

Decreased serum concentrations with strong CYP3A inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutin). Increased plasma concentrations of P-glycoprotein substrates (e.g. digoxin, colchicine, dabigatran) and CYP2D6 substrates (e.g. metoprolol).
Potentially Fatal: Increased serum concentration of eliglustat and may increase risk of cardiac arrhythmias with concomitant use of strong or moderate CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, bupropion, duloxetine, terbinafine) with strong or moderate CYP3A inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, lopinavir, cobicistat, conivaptan, boceprevir, ciprofloxacin, diltiazem, imatinib, cimetidine).

Increased plasma concentrations with grapefruit or grapefruit juice; avoid concomitant use. Decreased plasma concentrations with St. John’s wort.

Description:
Mechanism of Action: Eliglustat inhibits the enzyme glucosylceramide synthase thereby decreasing the rate of glycosphingolipid glucosylceramide formation which accumulates in target organs and causes complications in Gaucher disease type 1.
Pharmacokinetics:
Absorption: Systemic exposure depends on patient’s CYP2D6 phenotype; up to 9-fold higher in poor metabolisers. Bioavailability: <5% (extensive metabolisers). Time to peak plasma concentrations: 1.5-2 hours (extensive metabolisers); 2 hours (intermediate metabolisers); 3 hours (poor metabolisers).
Distribution: Volume of distribution: 835 L (extensive metabolisers). Plasma protein binding: 76-83%.
Metabolism: Extensively metabolised in the liver primarily by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites.
Excretion: Via urine (41.8%); faeces (51.4%) as inactive metabolites. Elimination half-life: 6.5 hours (extensive metabolisers); 8.9 hours (poor metabolisers).

Source: National Center for Biotechnology Information. PubChem Database. Eliglustat, CID=23652731, https://pubchem.ncbi.nlm.nih.gov/compound/Eliglustat (accessed on Jan. 22, 2020)

Store between 20-25°C.

Other Agents Affecting Metabolism

A16AX10 - eliglustat ; Belongs to the class of various alimentary tract and metabolism products.

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