NGF Blog


Gaucher Disease: Enzyme Replacement Therapy, Substrate Reduction Therapy & Potential Drug Interaction Side Effects

Substrate reduction therapy (SRT) first debuted as an alternative method of treating Gaucher disease in 2003. At that time, miglustat (Zavesca®) was the only known oral medication capable of managing Gaucher disease symptoms to prevent the condition from worsening. In 2014, the United States Food and Drug Administration (FDA) approved another oral SRT medication, eliglustat (Cerdelga®), for Gaucher disease type 1.

Like enzyme replacement therapy (ERT) treatments, FDA approved eliglustat as a first-line therapy for certain people living with Gaucher disease. Many people prefer SRT instead of ERT because it’s less invasive and usually more convenient to receive treatment.

But while SRT drugs revolutionized Gaucher disease treatment, these medications are not without risk. In some cases, patients report drug interactions while taking eliglustat. Depending on the interaction, serious side effects, such as cardiac issues, are possible.

Dr. Pramod Mistry, director of the National Gaucher Disease Treatment Center, professor of pediatrics and internal medicine, and chief of the Department of Pediatric GI/Hepatology at the Yale University School of Medicine, cautions, “Thanks to the success of treatments, we now have a population of patients who are older adults. In many cases, these patients take multiple medications to manage other health issues, such as depression or high blood pressure. The challenge is recognizing any potential drug interactions and taking action to prevent harm to the patient.”

Enzyme Replacement Therapy vs. Substrate Reduction Therapy

Traditionally, enzyme replacement therapy has been the standard treatment for Gaucher disease. Now, two SRT medications—miglustat and eliglustat—offer an alternative for some people diagnosed with Gaucher disease type 1.

Understanding enzyme replacement therapy

Given directly into the blood stream by infusion, ERT boosts levels of the enzyme glucocerebrosidase (GCase). Higher levels of GCase result in greater breakdown of glucocerebroside, a fatty chemical which builds up inside cells in people living with Gaucher disease. In turn, Gaucher disease patients experience less severe or fewer symptoms, and the progression of the disease may slow substantially.

But there are disadvantages to ERT. Generally, people living with Gaucher disease receive ERT infusions every two weeks. While some people receive infusions at home, many others travel to infusion centers, hospitals, or their physician’s offices to receive their treatment. This inconvenience, coupled with the invasiveness of the procedure, concerns some patients and caregivers. Additionally, ERT does not deliver as consistent a dose of medication compared to other treatments like substrate reduction therapy. As a result, patients may experience ups and downs where they feel best immediately after an infusion and not as well right before an infusion.

What is substrate reduction therapy?

In contrast to ERT, patients receiving SRT therapy, specifically eliglustat, typically take one or two capsules orally each day, which helps maintain a consistent dose of the medication within the body. When ingested, eliglustat helps prevent the production of the fatty chemical glucocerebroside. It doesn’t completely stop the production of glucocerebroside; rather, SRT helps the body keep glucocerebroside to manageable levels.

There are also disadvantages to SRT. Unlike ERT, some people receiving treatment with substrate reduction therapy report unpleasant side effects, such as:

  • Back pain
  • Diarrhea
  • Fatigue
  • Headache
  • Nausea
  • Pain in the upper abdomen and extremities

Additionally, some people find it difficult to stick to their treatment schedule. Some may stop taking their SRT medication because of side effects. Others simply forget to take their medication every day.

Why Doesn’t Everyone Use SRT?

If ERT is less convenient, more invasive, and doesn’t provide consistent dosing, shouldn’t all people diagnosed with Gaucher disease type 1 receive SRT? It may seem like this should be so, but only certain individuals can take SRT medications like eliglustat safely.

Metabolic profile testing

Within the body, certain substances, called enzymes, metabolize the medications a person takes. In other words, enzymes chemically change or break down any medications given to a person. One family of enzymes, known collectively as cytochrome P450 enzymes (CYP450), metabolize a wide variety of drugs. Some enzymes in this family, such as CYP2D6 and CYP3A4, metabolize more drugs than others.

CYP2D6—and to a lesser extent CYP3A4—both act to metabolize eliglustat. However, because these two enzymes also work on many other drugs, anyone considering SRT must undergo testing to determine their personal metabolic profile. Metabolic profile testing determines a person’s CYP2D6 metabolizer status with a simple blood test. The results show how effectively the individual’s body metabolizes certain drugs, including eliglustat.

“Eliglustat has been such a scientific leap in the treatment of Gaucher disease because it’s all about precision medicine. Before beginning treatment, we look at a person’s metabolizer status and other biomarkers to determine the right drug for the right patient at the right dose,” says Dr. Mistry.

In individuals who are poor, intermediate, or extensive metabolizers, eliglustat generally accumulates in high enough concentrations in the body to provide a therapeutic effect. But other people, known as ultra-rapid metabolizers, break down the drug more quickly. As a result, it may be much more difficult to achieve therapeutic concentrations of the medication in the blood stream. This means SRT may not be effective for ultra-rapid metabolizers.

Other contraindications to eliglustat

In addition to the results of metabolic profile testing, doctors use other factors to determine a person’s eligibility to begin SRT. Doctors don’t recommend SRT for:

  • Children or teenagers
  • People with liver or kidney disease
  • Pregnant or breastfeeding women
  • Most patients over age 65

Eliglustat and Drug Interactions

The same enzymes that break down eliglustat also act on other medications, including over-the-counter drugs and supplements. As a result, other medications, taken in conjunction with SRT, may affect how quickly the body metabolizes eliglustat.

Some SRT drugs can interact with medications such as antibiotics, cardiac drugs and antidepressants. Certain medications for depression may cause a 7.3-fold increase in eliglustat concentrations. Certain medications for depression, may cause a 7.3-fold increase in eliglustat concentrations. Others, including supplements such as St. John’s Wort, may decrease eliglustat concentrations by as much as 85%. Either way, certain drugs change how the body processes eliglustat—sometimes with dangerous consequences.

Cardiac problems

Dramatically increased eliglustat concentrations may affect the electrical systems which keep the heart beating in a normal, regular rhythm. Research shows that, at higher than usual concentrations, eliglustat may increase PR, QRS, and QTc intervals on an electrocardiogram (ECG). As a result, doctors don’t usually prescribe eliglustat for people who live with certain heart conditions, including:

  • Bradycardia
  • Congestive heart failure
  • Heart block
  • Long QT syndrome
  • Recent acute myocardial infarction (heart attack)

“When we begin a patient on eliglustat, we always get baseline lab work and ECGs to identify any rhythm abnormalities. But it’s important to keep in mind that prolonged heart rate intervals happen with a lot of drugs. We repeat ECGs every few weeks while the patient is first starting out on SRT therapy. Then, we continue to monitor each patient to make sure the medication concentration doesn’t exceed a certain limit. This makes cardiac problems much less likely,” says Dr. Mistry.

Using antibiotics

On their own, some antibiotics have been shown to prolong the heart’s QTc interval; however, this usually isn’t an issue since antibiotics are generally taken for short periods of time. But certain antibiotics, such as clarithromycin or ciprofloxacin, may increase eliglustat levels substantially. This, in turn, increases a person’s risk for cardiac issues.

“We know some types of antibiotics interact with eliglustat, but there are still some occasions where using an antibiotic is necessary. In these cases, we recommend temporarily stopping SRT to give the antibiotic time to work. Then, the patient can resume SRT safely,” says Dr. Mistry.

Grapefruit juice and supplements

Drug interactions aren’t limited to prescription medications. Supplements like St. John’s Wort reduce eliglustat concentrations, making the medication less effective. Conversely, supplements such as turmeric and beverages like grapefruit juice may increase eliglustat levels beyond the safety threshold.

Talking with Your Doctor

“Gaucher disease is extremely complex—because of this, people affected by the condition should go to a multidisciplinary expertise center. There, they can have a one-stop visit with multiple specialists, including doctors with expertise in Gaucher disease,” says Dr. Mistry.

“Since many OTC medications have the potential for drug interactions with eliglustat, it’s critically important to maintain a complete, current medication list for everyone we see.”

Each person receiving treatment for Gaucher disease should bring a complete medication list every time they visit a healthcare provider, including dentists. This list should include all prescription medications, over-the-counter drugs, and herbal supplements. Also, notify the healthcare team whenever starting or discontinuing any medications or supplements. This helps prevent potential drug interactions from occurring.

In Dr. Mistry’s own practice, no patients have taken eliglustat and developed major problems that caused alarm. This is thanks, in part, to the expertise of the multidisciplinary team, including pharmacists, who are also familiar with Gaucher disease type 1.

“SRT is a wonderful therapy for many who live with Gaucher disease. But it’s still important to report anything abnormal or unusual to your healthcare team, especially if you take multiple drugs. Sometimes, drug interactions are hard to predict, and frequent communication can help your doctor quickly adjust your treatment plan if an interaction occurs,” says Dr. Mistry.


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