Givinostat for Duchenne Muscular Dystrophy

Overview:

Givinostat, a histone deacetylase (HDAC) inhibitor, has emerged as a potential therapeutic avenue for Duchenne muscular dystrophy (DMD), a devastating genetic disorder characterized by progressive muscle degeneration and weakness. Clinical trials investigating Givinostat in DMD have shown promising results, with evidence suggesting improvements in muscle function and reduction in inflammation and fibrosis. By modulating gene expression and regulating key pathways involved in muscle regeneration and inflammation, Givinostat holds the potential to mitigate the progression of DMD. Givinostat was approved by the United States Food and Drug Administration (USFDA) in March 2024. Givinostat is given only to individuals more than six years of age.

Dosage and Route of Administration:

Before prescribing Givinostat, the platelet and triglyceride profile of the patient will be thoroughly assessed. The prescribed dosage of Givinostat should be given orally twice a day.

Givinostat is available as an oral suspension containing 8.86 mg/mL (milligrams per milliliter).

The prescribed dosage is:

• For patients weighing between 10 and 20 kilograms (22 to 44 pounds), the dosage is 22.5 mg twice daily. (The oral suspension volume is 2.5 mL twice daily).

• For individuals with a body weight between 20 and 40 kilograms (44 to 88 pounds), the dosage of Givinostat required is 31 mg twice daily. (Oral suspension volume is 3.5 mL twice daily).

• For people with weight between 40 and 60 kilograms (88 to 132 pounds), 44.3 mg of Givinostat is given two times a day, and the oral suspension volume is five milliliters twice daily.

• If the patient's body weight is more than 60 kilograms (132 pounds), the dose is 53.2 mg. (The oral suspension volume is six milliliters).

When there are any adverse effects after taking Givinostat, this prescribed dose will require modifications.

For Patients:

What Is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy is an infrequent genetic disorder that causes a compromise in the structural integrity of fibers forming a muscle. This progressively causes muscle degradation and weakness. The disease is noted in individuals within five years of age and is most commonly reported to have a male predilection. The main cause is the mutation in a protein called dystrophin. This protein makes a part of the dystrophin complex that is essential for stabilizing muscle fibers, including skeletal and cardiac muscles. Loss or mutation of this significant protein can lead to loss of muscle stabilization and can result in myofiber loss. Without dystrophin, muscles become increasingly damaged over time, leading to muscle weakness, difficulty walking, and eventual loss of ambulation (immobility). Also, Duchenne muscular dystrophy affects other important muscles all over the body, including those essential for breathing and the heart, which can result in complications in such vital systems.

What Are the Symptoms of Duchenne Muscular Dystrophy?

• Pain and weakness in muscles (especially hips, thighs, and shoulders).

• Difficulty standing up.

• Difficulty walking upstairs.

• Delayed milestones in children.

• Children may have a toe-walking gait.

• Motor skills will be affected.

• Muscle stiffness.

• Muscle contractures (shortened muscles and tendons).

• Changes in muscle bulk.

• Breathing issues.

• Difficulty coughing.

• Respiratory infections have become common.

• Weakened heart muscles.

• Irregular heartbeat.

• Variations in blood pressure levels.

Why Is Givinostat Given for Duchenne Muscular Dystrophy?

Givinostat is given for Duchenne muscular dystrophy to diminish the activity of histone deacetylase. Histone deacetylase plays a significant role in the pathogenesis of Duchenne muscular dystrophy, particularly in regulating gene expression and influencing cellular processes that are highly essential for muscle function. In Duchenne muscular dystrophy, the absence of dystrophin protein leads to a cascade of events, including chronic inflammation, oxidative stress (imbalance in the levels of reactive oxygen species), and impaired muscle regeneration and stabilization. Histone deacetylases, by removing acetyl groups from histone proteins, regulate chromatin structure and gene expression. In this genetic disease, there is a dysregulation of histone deacetylase activity, which has been implicated in promoting inflammation and fibrosis while inhibiting muscle regeneration. This dysregulation exacerbates the disease progression in Duchenne muscular dystrophy by contributing to muscle degeneration and weakness.

As a histone deacetylase (HDAC) inhibitor, Givinostat works by modulating gene expression and regulating pathways involved in muscle regeneration, inflammation, and fibrosis. By doing so, Givinostat has also been shown to improve muscle function. Thus, Givinostat is used in treating individuals with Duchenne muscular dystrophy.

How Should Givinostat Be Taken?

Oral suspension of Givinostat contains 8.86 milligrams of the drug per milliliter and appears white or pink in color. A single bottle of Givinostat contains 140 mL (milliliters) of the drug.

The oral suspension containing Givinostat should be shaken thoroughly (at least for 30 seconds) by inverting the bottle to 180 degrees. Once the suspension appears homogeneous, the appropriate prescribed volume of Givinostat should be taken orally from the suspension bottle with the help of a graduated syringe.

Missed Dose:

Any missed dose of Givinostat should not be taken again. Also, extra or double doses of Givinostat should never be taken.

Drug Storage:

The ideal temperature to store Givinostat is 68 to 77 degrees Fahrenheit (20 to 25 degrees Celsius).

Drug Disposal:

A bottle of Givinostat should not be kept for more than 60 days and should be disposed of with the help of a pharmacist.

What Are the Side Effects of Taking Givinostat?

• A significant side effect of taking Givinostat is hematologic changes. There can be a drastic drop in the platelet count after taking Givinostat. There can be a fall in the hemoglobin levels and white blood cell count (neutropenia). Other signs of myelosuppression are also noted along with Givinostat consumption.

• Increased levels of triglycerides are also noted with Givinostat administration. A level greater than 300 mg/dL (milligrams per deciliter) of triglycerides in the blood requires dose modification or cessation of the therapy.

• An electrocardiogram (ECG) shows prolongation of the QTc interval. This makes the individual prone to develop ventricular arrhythmias (dysregulated heart rhythm), thus resulting in life-threatening complications. This is specifically common among people with an existing medical history of cardiac dysfunction.

Other side effects noted are:

• Nosebleeds.

• Hematoma formation.

• Bleeding profusely from injury sites.

• Diarrhea.

• Nausea.

• Vomiting.

• Abdominal pain.

• Fatigue.

• Headache.

• Dizziness.

• Severe dehydration.

• Increased incidence of infections (due to neutropenia).

• Fever.

• Rashes.

• Joint pain.

• Decreased appetite.

• Reduced thyroxine hormone secretion (Hypothyroidism).

• Palpitation.

• Chest pain.

What Are the Precautions to Take Before Taking Givinostat?

• Hematological investigations should be taken before starting Givinostat treatment. This helps to keep an eye on the platelet count and other blood parameters. Heavy reduction in the platelet levels requires dose modification.

• Triglyceride levels in the body should be monitored continuously throughout the treatment with Givinostat. In the case of hypertriglyceridemia (increased triglyceride levels), the dosage of Givinostat will be reduced. If this persists even after reducing the dosage, Givinostat treatment will be stopped at once.

• ECG should be taken to look for any risk factors that could cause irregular heartbeats and other cardiac complications.

For Doctors:

Indications:

• The primary indication of Givinostat is Duchenne muscular dystrophy treatment.

• It is also being investigated for use in cancerous conditions, as well as other inflammatory diseases like Crohn’s disease (inflammation of bowel), juvenile rheumatoid arthritis (joint disease causing inflammation in children), and polycythemia vera (high erythrocyte count).

Contraindications:

• People with platelets (thrombocytes) count less than 150,000 cells per cubic millimeter.

• High triglyceride levels in the blood.

• Children less than six years of age.

Drug Ingredients:

Active Ingredient:

Givinostat hydrochloride monohydrate.

Inactive Ingredients:

Glycerine, sorbitol solution, polysorbate 20, sodium benzoate, tartaric acid, and saccharin sodium.

Clinical Pharmacology:

As a histone deacetylase inhibitor, Givinostat works by inhibiting the activity of histone deacetylase enzymes, leading to alterations in gene expression patterns and influencing various significant cellular processes such as proliferation, maturation, and plasma membrane stabilization.

Half-Life:

Givinostat has a half-life of six hours.

Pharmacokinetics:

Absorption:

After ingesting Givinostat through the oral route, the drug reaches the gastrointestinal tract and reaches maximum plasma levels within a few hours. The absorption of Givinostat is not significantly affected by food, allowing for flexible dosing options. Once absorbed, Givinostat enters systemic circulation, where it exerts its pharmacological effects by inhibiting histone deacetylase enzymes.

Distribution:

96 percent of Givinostat is bound to plasma protein. As a small molecule, Givinostat is likely to distribute widely into various tissues, including those affected by its therapeutic targets.

Metabolism:

Givinostat undergoes metabolism in the liver and forms various metabolites. These metabolites are less pharmacologically active than the parent compound. The main metabolite identified in human plasma is the hydroxylated derivative of Givinostat.

Elimination:

Following metabolism in the liver, both the parent compound and its metabolites are eliminated through biliary excretion into the gastrointestinal tract. Once in the intestine, Givinostat and its metabolites are then expelled from the body via feces. Less than three percent of Givinostat is excreted through urine.

Pharmacodynamics:

Givinostat promotes the acetylation of histone proteins, thereby loosening chromatin structure and facilitating transcriptional activation or repression of target genes. This mechanism allows Givinostat to regulate the expression of genes involved in important cell functions. Givinostat also suppresses the production and release of pro-inflammatory cytokines and chemokines. In diseases like Duchenne muscular dystrophy, Givinostat may promote muscle regeneration and reduce inflammation as well.

Clinical Toxicity:

• Givinostat can suppress the levels of thrombocytes in the blood.

• The presence of high levels of triglycerides is also noted in the circulating blood after treatment with Givinostat.

• Severe diarrhea is seen in people taking Givinostat.

• Prolongation of the QT interval followed by cardiac complications is also noted.

Drug dose modification of Givinostat is necessary in patients with less than 150,000 platelet cells per cubic millimeter for more than one week, severe diarrhea, and high fasting triglyceride levels (particularly above 300 mg/dL).

First Dose Modification:

• For people with weight ranging from 10 to 20 kilograms (22 to 44 pounds), the dose is 17.7 mg and the oral suspension volume is two milliliters two times a day.

• Individuals with a body weight between 20 and 40 kilograms (44 to 88 pounds), the dose is 22.5 mg twice daily. (The oral suspension volume is 2.5 mL twice daily).

• For a body weight between 40 and 60 kilograms (88 to 132 pounds), the dosage of Givinostat required is 31 mg twice daily. (Oral suspension volume is 3.5 mL twice daily).

• Patients weighing more than 60 kilograms (132 pounds), the dose given is 39.9 mg, and oral suspension volume is 4.5 mL taken twice daily.

If the adverse reactions persist even after modifying the dosage, a second modification becomes mandatory.

Second Dose Modification:

• For people with weight ranging from 10 to 20 kilograms(22 to 44 pounds), the dose is 13.3 mg and the oral suspension volume is 1.5 mL two times a day.

• People with a body weight between 20 and 40 kilograms (44 to 88 pounds), the dose is 17.7 mg twice daily. (The oral suspension volume is two mL twice daily).

• For a body weight between 40 and 60 kilograms (88 to 132 pounds), the dosage of Givinostat required is 26.6 mg twice daily. (Oral suspension volume is three mL twice daily).

• Patients weighing more than 60 kilograms (132 pounds), the dose given is 35.4 mg, and the oral suspension volume is four mL taken twice daily.

Drug Interactions:

• Givinostat is known to prolong the QT interval, so combining it with other medications known to cause QT prolongation or with drugs that can increase the risk of arrhythmias should be avoided.

• Using Givinostat with strong CYP3A4 inhibitors (For example, Itraconazole or Clarithromycin) increases the plasma levels of Givinostat. This can cause serious adverse effects.

Use in Specific Populations:

Pregnancy and Lactation

Animal studies showed impairment in the process of organogenesis, which resulted in fetal mortality or reduced birth weight. Neurological changes with cognitive decline were also noted in animals. However, there is no adequate evidence to support the use of Givinostat in pregnant ladies. Hence, the drug Givinostat is avoided in pregnant ladies. Lactating women are also prescribed Givinostat drugs due to a lack of research about the effects and secretion of Givinostat in breast milk.

Pediatric Population

Givinostat is advisable to be used in individuals older than six years of age. For children younger than six years, clinical trials are yet to be performed.

Geriatric Population

Duchenne muscular dystrophy is mainly a disease noted in young males and females. So, the effects of Givinostat on the geriatric population have not yet been studied.