Eliglustat - Dosage, Indications, Contraindications, and Side Effects

Overview

Eliglustat is a glucosylceramide synthase inhibitor indicated in adult patients for treating type I Gaucher disease. It was approved by the United States Food and Drug Administration (USFDA) on August 19th, 2014, and the European Medicines Agency (EMA) on January 19th, 2015. It is a prescription medicine, and the treatment must be supervised by a doctor with an experience in treating Gaucher's disease.

How Does Eliglustat Work?

Gaucher disease is characterized by the deficiency of the lysosomal enzyme acid beta-glucosidase, which catalyzes the conversion of glucocerebroside into glucose and ceramide. This leads to the accumulation of glucosylceramide. Eliglustat is an active ingredient in the drug, which works by blocking the action of an enzyme glucosylceramide synthase, responsible for the production of glucosylceramide fat, thereby preventing the fat buildup in the organs such as the spleen, liver, bones, etc., and helping them to function better.

What Are the Indications for Eliglustat?

• Eliglustat is indicated in adult patients for the long-term treatment of Gaucher disease type I who are extensive metabolizers of the enzyme CYP2D6 or intermediate or poor metabolizers, which are detected by an FDA-cleared test.

• Dose limitations include the patients who are ultra-rapid metabolizers of CYP2D6 and may not get adequate concentrations of Eliglustat to achieve the therapeutic effect. A specific dose of Eliglustat cannot be recommended for patients who are intermediate metabolizers and whose CYP2D6 genotype cannot be determined.

What Are the Contraindications to Eliglustat?

Contraindications to Eliglustat include;

• Patients who are intermediate or poor metabolizers taking strong CYP3A inhibitors.

• Patients who are extensive metabolizers or intermediate metabolizers who take strong or moderate CYP2D6 inhibitors in combination with strong or moderate CYP3A inhibitors.

What Is the Dosage of Eliglustat?

Patients are selected based on their CYP2D6 metabolizer status, established by an FDA-cleared test that determines the specific genotype. Eliglustat is recommended at a dose of 84 mg (milligrams) twice daily, along with monitoring for adverse effects. Concomitant administration of this drug with other CYP2D6 or CYP3A inhibitors may require adjustments in the dose to reduce the potential risk of adverse reactions.

What Are the Drug Warnings and Precautions?

• Eliglustat gets metabolized through CYP2D6 and CYP3A pathways, and the drugs that inhibit these pathways may increase the exposure to Eliglustat and cause prolongation of cardiac intervals, which may result in cardiac arrhythmias. Hence, drugs that inhibit CYP2D6 and CYP3A are contraindicated with Eliglustat, depending on the CYP2D6 metabolizer status.

• The use of Eliglustat in patients with a history of cardiac diseases such as congestive cardiac failure, acute myocardial infarction, heart block, ventricular arrhythmia, bradycardia, etc., has not been determined, as Eliglustat is suspected to increase ECG intervals such as PR, QTc, and QRS at elevated Eliglustat plasma concentrations and along with antiarrhythmic medications.

What Are the Adverse Effects of Eliglustat?

Adverse effects of Eliglustat include;

• Headache.

• Arthralgia (joint pain).

• Flatulence (accumulation of gas in the digestive tract).

• Fatigue.

• Migraine (severe headache).

• Backache.

• Nausea.

• Diarrhea.

• Upper abdominal pain.

• Pain in the extremities.

For Patients

What Is Gaucher Disease?

Gaucher disease is a rare genetic metabolic disorder that results from a deficiency of the enzyme beta-glucosidase, which is responsible for controlling the levels of glucocerebroside as a result of large quantities of fatty substances accumulating in the bone marrow, liver, and spleen. It causes symptoms such as anemia, tiredness, bone pain, easy bruising, etc. It adversely affects the quality of life in adults and children; it can cause retarded growth and delayed puberty.

What Is Eliglustat?

Eliglustat is a medical treatment for type I Gaucher disease in adults. This medicine can only be obtained with a prescription, and the treatment must be started by a doctor who is experienced in the management of such rare disorders.

How Is Eliglustat Stored?

Eliglustat is available as hard gelatin capsules and must be stored at room temperature between 20 and 25 degrees Celsius, out of reach of children.

What Are the Instructions for Patients Before Taking Eliglustat?

• Eliglustat capsules must be swallowed whole, preferably with water. The medicine must not be crushed or dissolved, and the contents must not be opened.

• It can be taken with or without food.

• If a dose is missed, the prescribed dose must be taken at the next regularly scheduled interval, and the dose must not be doubled.

• Consumption of grapefruit or its juice must be avoided during the treatment with Eliglustat.

What Must the Patients Inform the Doctor Before Taking Eliglustat?

• Patients with a history of cardiac diseases, such as congestive cardiac failure, bradycardia, heart block, etc., must inform their healthcare provider before beginning treatment with Eliglustat.

• If the patient develops symptoms such as dizziness, fainting, palpitations, etc., the doctor must be informed immediately.

• Patients must inform the doctor if they have any liver disorders in order to plan the treatment.

• Female patients must inform the doctor if they are pregnant, planning to become pregnant, or breastfeeding before the treatment.

• Patients must inform the doctor if they take other medications, over-the-counter (OTC) drugs, or herbal or vitamin supplements.

What Are the Side Effects of Eliglustat?

The side effects of Eliglustat include;

• Nausea.

• Headache.

• Diarrhea.

• Back pain.

• Stomach pain.

• Migraine.

• Pain in the legs and arms.

• Joint pain.

• Gastric issues.

• Rash.

For Doctors

Description

Eliglustat is a glucosylceramide synthase inhibitor, and patients are selected based on the FDA-genotyping test to establish the CYP2D6 metabolizers. The test results dictate the dosing in the individuals. Eliglustat capsules contain Eliglustat tartrate as an active ingredient and inactive ingredients such as lactose monohydrate, glyceryl behenate, hypromellose, microcrystalline cellulose, etc.

Clinical Pharmacology

Mechanism of Action

Gaucher disease is characterized by the deficiency of the lysosomal enzyme acid beta-glucosidase, which causes the accumulation of glucosylceramide in the macrophages, leading to Gaucher cells' formation. Eliglustat is a specific inhibitor of glucosylceramide synthase, and reduces the production of glucosylceramide, thus lowering the levels and balancing the deficiency of beta-glucosidase.

Pharmacokinetics

• Absorption: The time taken to attain the maximum plasma concentration (Tmax) in CYP2D6 extensive metabolizers (EMs) is approximately 1.5 to 2 hours, with a maximum plasma concentration (Cmax) of the drug ranging between 12.1 and 25 ng/ml. It has been noticed that EMs have a low bioavailability of less than five percent, which indicates extensive first-pass metabolism in the liver. In poor metabolizers (PMs), the Tmax is around three hours, and the corresponding Cmax range is 113 to 137 ng/ml. Studies have suggested that the coadministration of Eliglustat with a high-fat meal decreases Cmax by about 15 percent. However, there was no change in the area under the curve (AUC) and no clinically relevant effect of food on the pharmacokinetics of the drug.

• Distribution: After absorption, the drug reaches the plasma, where approximately 76 to 83 percent of the drug remains bound to plasma proteins. The volume of distribution is around 835 L in those with EMs of CYP2D6, signifying the main distribution in plasma.

• Metabolism: The drug's metabolism occurs predominantly in the liver through the cytochrome enzyme CYP2D6 and, to a limited extent, through CYP3A4. It involves mainly a pathway of sequential oxidation leading to the generation of oxidative metabolites. The other parameters, such as age, gender, race, body weight, or mild renal impairment, have no clinical impact.

Pharmacodynamics

A double-blind, single dose, placebo, and positively controlled study in 42 subjects was conducted, which indicated a concentration-related increase in cardiac intervals such as PR, QTc, and QRS. At the highest mean concentration of 237 ng/ml after a single therapeutic dose, it was observed that Eliglustat did not prolong the QT or QTc interval to a clinically significant extent.

Results of Clinical Studies

A randomized placebo-controlled double-blind study was conducted across several centers to assess the safety and efficacy of 40 Gaucher disease patients above 16 years of age.

The treatment group received 42mg of the standard dose twice daily, gradually increasing the dose at week four to 84 mg twice daily. The result was a change in spleen volume in comparison to the placebo.

Hemoglobin levels and a percentage change in platelet count and liver volume were assessed as secondary endpoints. In uncontrolled studies, the improvement noticed in the treatment group was sustained for up to four years. In a second trial, which was a randomized, multicenter, open-label study assessing the non-inferiority of Eliglustat in comparison to treatment with enzyme replacement therapy for Gaucher disease, After one year of treatment with the drug, almost 85 percent of patients reported an improvement, compared to 93.6 percent in the Imiglucerase treatment group.

Non-Clinical Toxicology

• Carcinogenesis: The carcinogenic effect of the drug was assessed by administering 75 mg/kg/day of Eliglustat to male rats and 50 mg/kg/day to female rats. No neoplasm was observed that was related to the treatment.

• Mutagenesis: The Ames test and chromosomal aberration test using human blood lymphocytes in the periphery were used to assess mutagenicity, but no positive result was reported. Other tests, such as the micronucleus test and gene mutation assay, were also negative.

• Fertility: The administration of Eliglustat at 30 mg/kg, which is 1.5 times the dose recommended in humans, increased implantation loss in early embryonic studies conducted in female rats. Similar results were also noticed with a dose of 100 mg/kg which is five times the human-recommended dose. Studies in monkeys also demonstrated similar adverse effects at a 70 mg/kg dose, approximately seven times the dose recommended in humans.

Drug Interactions

• Eliglustat is a substrate of CYP2D6 and CYP3A; hence, co-administration of drugs that inhibit these pathways is contraindicated with Eliglustat. It is also dependent on the CYP2D6 metabolizer status, as it can cause an increase in Eliglustat exposure, resulting in a prolongation of cardiac intervals that may lead to cardiac arrhythmias. Therefore, dose adjustments may be made with certain drugs to reduce the risk of adverse reactions.

• Administration of Eliglustat and strong CYP3A inducers such as Rifampicin, Phenytoin, Carbamazepine, etc., is not recommended as it can reduce the exposure to Eliglustat.

• Coadministration of Eliglustat with drugs such as Digoxin (P-gp substrate) and CYP2D6 substrates such as Metoprolol, Nortriptyline, Chlorpromazine, etc. may cause increased concentrations of the concomitant drug. Therefore, serum Digoxin concentrations must be monitored before starting the treatment with Eliglustat, the Digoxin dose must be reduced by about 30 percent, and the patient must be monitored regularly thereafter.

• For patients under the treatment of drugs such as Imiglucerase, Taliglucerase alfa, or Velaglucerase alfa, Eliglustat must be administered 24 hours after the last dose of the previous treatment.

Use of Eliglustat in Specific Populations

• Pregnancy: Female patients with Gaucher disease have an increased risk of spontaneous abortion if the disease is not appropriately managed or the symptoms are not controlled during pregnancy. It may cause hepatosplenomegaly, which may interfere with pregnancy and can result in bleeding and hemorrhage.

Eliglustat may be recommended during pregnancy only if the potential benefit justifies the potential risk to the fetus, as neither adequate data nor well-controlled studies have been performed on pregnant women. However, animal studies suggest that anomalies were observed at six times the human-recommended dose in rats, and no fetal harm was reported when Eliglustat was administered to pregnant rabbits at ten times the recommended human dose.

• Lactating Mothers: The presence of Eliglustat in breast milk is not known; however, many drugs have the potential to pass into breast milk. To avoid adverse effects on the infants, a decision must be made whether to discontinue breastfeeding or stop the drug, owing to the importance of the drug to the lactating mother.

• Pediatric Use: The safety and effectiveness of Eliglustat have not been established in pediatric patients.

• Geriatric Use: Subjects above 65 were not included in the clinical studies to determine the response compared to the younger individuals.

• Renal Impairment: No adjustments in the dose of Eliglustat are required for patients with mild renal disorders. However, it is not recommended in patients with moderate to severe renal impairment, as the drug has not been studied in such patients.

• Hepatic Impairment: As the drug has not been studied in patients with liver disorders, Eliglustat is not recommended in patients with any stage of hepatic impairment or cirrhosis.

• Poor Metabolizers: Adverse drug monitoring is required in patients with poor metabolizers, as 84 mg of Eliglustat has not been studied in such patients.