Eliglustat

Eliglustat is a Glucosylceramide Synthase Inhibitor belonging to Drug for Genetic disorder.

Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers.

Eliglustat systemic exposure depends on patient’s CYP2D6 phenotype; up to 9-fold higher in poor metabolisers. The Bioavailability is about <5% (extensive metabolisers). Time to peak plasma concentrations: 1.5-2 hours (extensive metabolisers); 2 hours (intermediate metabolisers); 3 hours (poor metabolisers). The Volume of distribution is approximately 835 L (extensive metabolisers). The Plasma protein binding is 76-83%. Eliglustat extensively metabolised in the liver primarily by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites. Eliglustat excreted via urine (41.8%); faeces (51.4%) as inactive metabolites. The Elimination half-life is about 6.5 hours (extensive metabolisers) and 8.9 hours (poor metabolisers).

Eliglustat shows side effects like Nausea, stomach pain, dizziness, excessive tiredness, headache, muscle tightening, joint pain.

Eliglustat is available in the form of Capsule.

Eliglustat is available in India, US, UK, Singapore, Malaysia, Canada, France, Italy, Spain, and Australia.

Eliglustat belongs to the Drug for Genetic disorder acts as a Glucosylceramide Synthase Inhibitor.

Eliglustat is a glucosylceramide synthase inhibitor used for the treatment of type 1 Gaucher disease. Gaucher disease is a rare genetic disorder characterized by the deficiency of acid β-glucosidase, an enzyme that converts glucosylceramide (also known as glucocerebroside) into glucose and ceramide. In patients with Gaucher disease, glucosylceramide is accumulated in the lysosomes of macrophages, leading to the formation of foam cells or Gaucher cells. Gaucher cells infiltrate the liver, spleen, bone marrow and other organs, leading to complications such as anemia, thrombocytopenia, and hepatosplenomegaly. Eliglustat reduces the production of glucosylceramide by inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids. This lowers the amount of glucosylceramide that is available in lysosomes and balances the deficiency of acid β-glucosidase.

The Data of Onset and duration of action of Eliglustat is not clinically established.

The Tmax of Eliglustat is approximately 1.5 to 2 hours by extensive metabolisers (Ems); 2 hours by intermediate metabolisers (IMs) and 3 hours by poor metabolisers (PMs).

Eliglustat is available in the form of Oral Capsule.

Eliglustat tablet is taken orally, usually once or twice daily.

Eliglustat is used to treat Gaucher disease type 1 (a condition in which a certain fatty substance is not broken down normally in the body and builds up in some organs and causes liver, spleen, bone, and blood problems) in certain people.

Eliglustat is a Glucosylceramide Synthase Inhibitor belonging to Drug for Genetic disorder.

Eliglustat is in a class of medications called enzyme inhibitors. It works by preventing the body from producing the fatty substance so that less of it will build up in the body and cause symptoms.

Eliglustat is approved for use in the following clinical indications

• Gaucher disease:

Eliglustat is used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers.

• Gaucher disease:

Adult Oral Dose:

EMs and IMs (Extensive and intermediate metabolizers): 84 mg twice daily.

PMs (Poor metabolizers): 84 mg once daily.

Eliglustat is available in the form of Oral Capsule.

• Dosage Adjustment in Kidney Patient

Mild to severe renal impairment (CrCl ≥15 mL/minute):

Extensive metabolizers (EMs): No dosage adjustment necessary.

Intermediate metabolizers (IMs) and poor metabolizers (PMs): Avoid use.

ESRD (CrCl <15 mL/minute with or without dialysis):

EMs, IMs, and PMs: Avoid use.

• Dosage Adjustment in Hepatic impairment Patient

Mild hepatic impairment (Child-Pugh class A):

Extensive metabolizers (EMs) (without concomitant use of CYP2D6 or CYP3A inhibitors): No dosage adjustment necessary.

EMs taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A4 inhibitor: 84 mg once daily.

EMs taking a strong or moderate CYP2D6 inhibitor: Use is contraindicated.

Intermediate metabolizers (IMs): Use is contraindicated.

Poor metabolizers (PMs): Use is contraindicated.

Moderate to severe hepatic impairment (Child-Pugh class B and C):

EMs, IMs, and PMs: Use is contraindicated.

Eliglustat serum concentrations may be increased when taken with grapefruit or grapefruit juice.

Management: Avoid concurrent use.

Eliglustat is contraindicated in patients with

• Use in extensive metabolizers (EMs) with moderate or severe hepatic impairment.
• Use in intermediate metabolizers (IMs) or poor metabolizers (PMs) with any degree of hepatic impairment.
• Concomitant use of a moderate or strong CYP2D6 inhibitor with a moderate or strong CYP3A inhibitor in EMs or IMs
• Concomitant use of a strong CYP3A inhibitor in PMs or IMs
• Concomitant use of a moderate or strong CYP2D6 inhibitor in EMs with mild hepatic impairment.

• Arrhythmias: May cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations.
• Cardiovascular disease: Avoid use in patients with preexisting cardiac disease (CHF, recent acute MI, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (eg, quinidine, procainamide) and Class III (eg, amiodarone, sotalol) antiarrhythmic medications.

There are no human data available on the presence of eliglustat in human milk, the effects on the breastfed infant, or the effects on milk production. Eliglustat and its metabolites were present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Eliglustat and any potential adverse effects on the breastfed child from Eliglustat or from the underlying maternal condition.

Adverse events were observed in some animal reproduction studies. Uncontrolled type 1 Gaucher disease is associated with an increased risk of spontaneous abortion; maternal hepatosplenomegaly and thrombocytopenia may also occur and lead to adverse pregnancy outcomes.

Eliglustat serum concentrations may be increased when taken with grapefruit or grapefruit juice.

Management: Avoid concurrent use.

• Common

Headache, fatigue, Diarrhea, nausea, arthralgia, back pain, limb pain.

• Rare

Palpitations, Migraine, dizziness, Skin rash, Flatulence, upper abdominal pain, dyspepsia, gastroesophageal reflux disease, constipation, Weakness, Oropharyngeal pain, cough.

• Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg.
• Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors.
• Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a P-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details.
• CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs.
• CYP2D6 Inhibitors (Strong): May increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs.
• Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate.
• Darunavir: May increase the serum concentration of Eliglustat.
• Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency.
• Doxorubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Doxorubicin (Conventional).
• Doxorubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Doxorubicin (Liposomal).
• Itraconazole: May increase the serum concentration of Eliglustat. Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with itraconazole. Use of eliglustat is contraindicated during and for 2 weeks after itraconazole in CYP2D6 IMs, PMs, or in CYP2D6 EMs who are also taking strong or moderate CYP2D6 inhibitors.
• Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib.
• Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.
• Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects.
• Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication.
• Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
• Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor.
• Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor.

The common side effects of Eliglustat include the following

• Common side effects

Fatigue, weakness, joint pain, headache, migraine, nausea, heartburn, gas, mouth and throat pain, diarrhea, back pain, pain in legs or arms, stomach pain, cough, rash.

• Rare side effects

Heart palpitations, dizziness, or fainting.

• Pregnancy

Pregnancy Category C

Available data on Eliglustat use in pregnant women includes 20 pregnancies that occurred during the clinical development program and a small number of post-marketing case reports. These data are not sufficient to assess drug-associated risks major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats administered oral eliglustat during organogenesis, a spectrum of various developmental abnormalities was observed at doses 6 times the recommended human dose. No adverse developmental outcomes were observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose.

• Nursing Mothers

There are no human data available on the presence of eliglustat in human milk, the effects on the breastfed infant, or the effects on milk production. Eliglustat and its metabolites were present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Eliglustat and any potential adverse effects on the breastfed child from Eliglustat or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Clinical studies of Eliglustat did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients.

Symptoms: Dizziness marked by disequilibrium, hypotension, bradycardia, nausea, vomiting.

Management: Symptomatic and supportive treatment.

Pharmacodynamic

Effects on spleen and liver volume, hemoglobin, and platelets increased with increasing steady state average trough concentrations of eliglustat ranging up to 14 ng/mL in treatment naive patients in Trial 1. In patients previously treated with enzyme-replacement therapy in Trial 2, no clinically relevant exposure-response relationship was observed.

• Cardiac Electrophysiology

Concentration-related increases were observed for the placebo-corrected change from baseline in the PR, QRS, and QTc intervals. At the mean peak concentration of 237 ng/mL at a dose of 800 mg eliglustat tartrate (8 times the recommended dose), Eliglustat did not prolong the QT/QTc interval to any clinically relevant extent. However, pharmacokinetic/pharmacodynamic modeling predicts mean (upper bound of the 95% one-sided confidence interval) increases in the PR, QRS, and QTcF intervals of 22 (26), 7 (10), and 13 (19) msec, respectively, at eliglustat plasma concentration of 500 ng/mL.

Pharmacokinetics

• Absorption

Eliglustat systemic exposure depends on patient’s CYP2D6 phenotype; up to 9-fold higher in poor metabolizers. Bioavailability: <5% (extensive metabolizers). Time to peak plasma concentrations: 1.5-2 hours (extensive metabolizers); 2 hours (intermediate metabolizers); 3 hours (poor metabolizers).

• Distribution

The Volume of distribution is approximately 835 L (extensive metabolizers). The Plasma protein binding is 76-83%.

• Metabolism and Excretion

Eliglustat extensively metabolized in the liver primarily by CYP2D6 and to a lesser extent by CYP3A4 to inactive metabolites. Eliglustat excreted via urine (41.8%); faeces (51.4%) as inactive metabolites. The Elimination half-life is about 6.5 hours (extensive metabolizers) and 8.9 hours (poor metabolizers).

• https://www.uptodate.com/contents/eliglustat-drug-information#F25733605
• https://go.drugbank.com/drugs/DB09039
• https://www.drugs.com/dosage/eliglustat.html
• https://www.mims.com/indonesia/drug/info/eliglustat?mtype=generic
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205494s003lbl.pdf
• https://medlineplus.gov/druginfo/meds/a618038.html#side-effects
• https://www.rxlist.com/cerdelga-drug.htm#clinpharm