Eliglustat response

Synonyms: Cerdelga response

Summary

Eliglustat 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. 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 disease and –– unlike Gaucher types 2 and 3 –– does not directly affect the central nervous system primarily. Eliglustat, a ceramide mimic, inhibits the enzyme that synthesizes glucosylceramides (UDP-Glucose Ceramide Glucosyltransferase), thereby reducing the accumulation of these lipids in the lysosome. Eliglustat is broken down to inactive metabolites by CYP2D6 and, to a lesser extent, CYP3A. The dosage of eliglustat is based on the individual’s CYP2D6 metabolizer status. Individuals with normal CYP2D6 activity are termed normal metabolizers (NM), those with reduced activity are termed intermediate metabolizers (IM), and if activity is absent, poor metabolizers (PM). The FDA-approved drug label for eliglustat provides specific dosage guidelines based on their CYP2D6 status and concomitant usage of CYP2D6 or CYP3A inhibitors, and states that hepatic and renal function should also be considered when determining the appropriate dosage. The label also states that CYP2D6 ultrarapid metabolizers (UM) may not achieve adequate concentrations of eliglustat for a therapeutic effect, and that for individuals for whom a CYP2D6 genotype cannot be determined, a specific dosage cannot be recommended. Dosing recommendations for eliglustat have also been published by the Dutch Pharmacogenetics Working Group (DPWG) based on CYP2D6 metabolizer type and include dose adjustments for dosing eliglustat with medications that alter CYP2D6 and or CYP3A function. [from Medical Genetics Summaries]

Available tests

10 tests are in the database for this condition.

Clinical tests (10 available)

Molecular Genetics Tests

Genes See tests for all associated and related genes

Associated genes Help
Genes reported to contribute to the condition.

CYP2D6
121 tests
Also known as: CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6, P450-DB1, P450C2D, P450DB1, CYP2D6
Summary: cytochrome P450 family 2 subfamily D member 6

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted¹information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2018 Statement from the US Food and Drug Administration (FDA):

The recommended dosage of Eliglustat in adults is based on the patient's CYP2D6 metabolizer status.

[…]

Reduce dosage frequency of Eliglustat 84 mg to once daily in CYP2D6 NMs and IMs with or without hepatic impairment taking CYP2D6 or CYP3A inhibitors.

Table [5]: Recommended Dosage of Eliglustat: 84 mg Once Daily based on CYP2D6 Metabolizer, Hepatic Impairment Status, and Concomitant CYP Inhibitors

CYP2D6 Metabolizer Status	Hepatic Impairment Status	Concomitant CYP Inhibitor
NMs	Without Hepatic Impairment	Taking a strong or moderate CYP2D6 inhibitor Taking a strong or moderate CYP3A inhibitor
NMs	Mild (Child-Pugh Class A) Hepatic Impairment	Taking a weak CYP2D6 inhibitor Taking a strong, moderate, or weak CYP3A inhibitor
IMs	Without hepatic involvement	Taking a strong or moderate CYP2D6 inhibitor

4 CONTRAINDICATIONS

Eliglustat is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals.

NMs

Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
Moderate or severe hepatic impairment
Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor

IMs

Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
Taking a strong CYP3A inhibitor Any degree of hepatic impairment

PMs

Taking a strong CYP3A inhibitor
Any degree of hepatic impairment

7 DRUG INTERACTIONS

7.1 Effect of other drugs on Eliglustat

Coadministration of Eliglustat with:

CYP2D6 or CYP3A inhibitors may increase eliglustat concentrations which may increase the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac interval.
strong CYP3A inducers decreases eliglustat concentrations which may reduce efficacy.

Table [6]: Prevention and Management Strategies of Drug Interactions Affecting eliglustat based on CYP2D6 Metabolizer status and Concomitant Interacting drug

Concomitant Drug(s)	CYP2D6 Metabolizer Status
* . No effect of CYP2D6 inhibitor due to little or no CYP2D6 activity in CYP2D6 PMs.
Concomitant Drug(s)	NMs	IMs	PMs
CYP2D6 Inhibitor
Strong	Reduce frequency of eliglustat 84mg to once daily		Continue eliglustat 84mg once daily*
Moderate	Reduce frequency of eliglustat 84mg to once daily
Weak	Continue eliglustat 84mg twice daily
CYP3A Inhibitor
Strong	Reduce frequency of eliglustat 84 mg to once daily	Contraindicated
Moderate	Reduce frequency of eliglustat 84 mg to once daily	Avoid coadministration.
Weak	Continue eliglustat 84mg twice daily		Avoid coadministration.
CYP2D6 Inhibitor Concomitantly with a strong CYP3A Inhibitor
Strong	Contraindicated
Moderate	Contraindicated
CYP2D6 Inhibitor Concomitantly with a moderate CYP3A Inhibitor
Strong	Contraindicated		Avoid coadministration
Moderate	Contraindicated		Avoid coadministration
CYP3A Inducer
Strong	Avoid coadministration

8 Use In Specific Populations

8.6 Renal Impairment

Use eliglustat in patients with renal impairment based on the patient's CYP2D6 metabolizer status

NMs

Avoid eliglustat in patients with end-stage renal disease (ESRD) (estimated creatinine clearance (eCLcr) less than 15 mL/min not on dialysis or requiring dialysis).
No dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment (eCLcr at least 15 mL/min).

IMs and PMs

Avoid eliglustat in patients with any degree of renal impairment.

8.7 Hepatic Impairment

Use eliglustat in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors

NMs

Eliglustat is contraindicated in patients with [see Contraindications]:

severe (Child-Pugh Class C) hepatic impairment
moderate (Child-Pugh Class B) hepatic impairment
mild (Child-Pugh Class A) hepatic impairment taking a strong or moderate CYP2D6 inhibitor

Reduce dosage frequency of eliglustat 84 mg to once daily [see Dosage and Administration] in patients with mild hepatic impairment taking:

a weak CYP2D6 inhibitor
a strong, moderate, or weak CYP3A inhibitor

No dosage adjustment is recommended in patients with mild hepatic impairment, unless otherwise specified above.

IMs and PMs

Eliglustat is contraindicated in patients with any degree of hepatic impairment [see Contraindications].Please review the complete therapeutic recommendations that are located here: (1).

2018 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

CYP2D6 UM:

Eliglustat is contra-indicated.

choose an alternative if possible

CYP2D6 IM:

Recommendation:

Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR: Eliglustat is contra-indicated.
1. choose an alternative if possible

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):
1. use a dose of 84 mg eliglustat 1x daily
Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):
1. consider a dose of 84 mg eliglustat 1x daily
2. be alert to side effects
Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

-1. choose an alternative if possible

if an alternative is not an option:
consider a dose of 84 mg eliglustat 1x daily
be alert to side effects
- Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):
  1. choose an alternative
  2. if an alternative is not an option:
    1. consider a dose of 84 mg eliglustat 1x daily
    2. be alert to side effects
- Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.
  1. choose an alternative if possible
- NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:
  1. use the standard dose of 84 mg 2x daily

CYP2D6 PM:

Recommendation:

Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

Eliglustat is contra-indicated.

choose an alternative if possible
- Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

Eliglustat is not recommended.

choose an alternative if possible
- Co-medication with a WEAK CYP3A INHIBITOR (for example amlopidine [amlodipine], cilostazole [cilostazol], fluvoxamine, goldenseal, isoniazide [isoniazid], ranitidine, ranolazine):
  1. choose an alternative for the weak CYP3A inhibitor if possible
  2. if an alternative is not an option:
    1. use a dose of 84 mg eliglustat 1x daily
    2. be alert to side effects
- Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum):

Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

choose an alternative if possible
- NO co-medication with a CYP3A inhibitor or strong CYP3A inducer:
  1. use a dose of 84 mg 1x daily

Please review the complete therapeutic recommendations that are located here:(4).

¹ The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance with nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.

Reviews

Clinical resources

Practice guidelines

DPWG, 2023
Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Recommendation.
DailyMed Drug Label, 2021
DailyMed Drug Label, CERDELGA, 2021

Molecular resources

Consumer resources

MedlinePlus

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