ataluren

Action and Spectrum

Actions and Spectrum: 

The mechanism of action of ataluren involves promoting the readthrough of premature termination codons (PTCs), which are the signals that instruct the ribosome to stop protein synthesis prematurely. ataluren specifically targets PTCs and allows the ribosome to continue protein synthesis past the PTC, producing full-length, functional proteins instead of truncated, non-functional proteins.

This can restore the normal functioning of the affected protein and potentially alleviate the symptoms of the genetic disorder. The spectrum of activity of ataluren is limited to genetic disorders caused by nonsense mutations. It effectively treats specific forms of DMD, CF, and inherited retinal dystrophy caused by nonsense mutations in the relevant genes. ataluren is inadequate for other genetic mutations or diseases not caused by mutations in the genes targeted ataluren. 

Drug Interaction

Adverse Reaction

Black Box Warning

Contraindication / Caution

Contraindications/caution: 

• Nonsense mutation type: ataluren is indicated for specific genetic disorders caused by nonsense mutations, including Duchenne muscular dystrophy (DMD) in ambulatory patients (able to walk) and cystic fibrosis (CF) in patients with specific mutations. It should not be used for other types of mutations or genetic disorders. 
• Age: ataluren is generally indicated for use in patients two years of age and older with DMD and five years of age and older with CF. Safety and efficacy in pediatric patients younger than two years of age with DMD or younger than five with CF have not been established. 
• Renal or hepatic impairment: ataluren should be used cautiously in patients with moderate to severe renal or hepatic impairment, as the safety and efficacy in these populations have not been well studied. 
• Drug interactions: ataluren may interact with certain medications, and concomitant use should be done cautiously.  
• Pregnancy and breastfeeding: The safety of ataluren during pregnancy and breastfeeding has not been established. It should be used cautiously in pregnant or breastfeeding individuals only if the potential benefit justifies the potential risk to the fetus or infant. 
• Adverse reactions: ataluren may cause specific adverse reactions, such as gastrointestinal symptoms (e.g., diarrhea, nausea), central nervous system effects (e.g., headache, dizziness), and others. These should be monitored and managed appropriately. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.   

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

ataluren is a medication used to treat genetic disorders caused by nonsense mutations, which are specific types of mutations in the DNA that result in the premature termination of protein synthesis. ataluren promotes the “readthrough” of these premature stop codons, allowing the protein synthesis to continue beyond the mutated region and produce a full-length functional protein. This mechanism of action makes ataluren unique among other types of drugs. 

The exact pharmacological mechanism of ataluren has yet to be fully understood. Still, it is thought to work by binding to the ribosome, the cellular structure responsible for protein synthesis, and facilitating the insertion of an amino acid at the site of the nonsense mutation. This allows the ribosome to bypass the premature stop codon and continue protein synthesis, producing a functional protein. 

ataluren is effective in treating certain genetic disorders caused by nonsense mutations, including Duchenne muscular dystrophy (DMD) in ambulatory patients (able to walk) and cystic fibrosis (CF) in patients with specific mutations. 

Pharmacodynamics: 

Nonsense mutation readthrough: ataluren is thought to bind to the ribosome, the cellular structure responsible for protein synthesis, and facilitate the insertion of an amino acid at the site of the premature stop codon in the mRNA. This allows the ribosome to bypass the premature stop codon and continue protein synthesis, producing a full-length functional protein. 

mRNA surveillance mechanisms: ataluren may also interfere with cellular mRNA surveillance mechanisms, which detect and degrade abnormal mRNA molecules that contain premature stop codons. By inhibiting mRNA surveillance, ataluren may increase the stability of the mRNA with nonsense mutations, allowing it to be translated into a functional protein. 

Cellular and tissue effects: ataluren’s pharmacodynamics may vary depending on the specific cell type and tissue where it is administered. Depending on tissue permeability, drug distribution, and cellular uptake, it may exert its effects locally at the administration site or systemically in different tissues throughout the body. 

Genetic disorder-specific effects: ataluren’s pharmacodynamics may also be influenced by the specific genetic disorder being treated. Different nonsense mutations and underlying genetic conditions may have variable responses to ataluren treatment. The exact mechanism of action and pharmacodynamic effects of ataluren may differ depending on the targeted genetic disorder, such as Duchenne muscular dystrophy (DMD) or cystic fibrosis (CF). 

Pharmacokinetics: 

Absorption 

ataluren is administered orally as a tablet or powder for suspension. It is rapidly absorbed from the gastrointestinal tract after oral administration, but its absolute bioavailability is low and variable, ranging from approximately 40% to 90%. Food can affect the absorption of ataluren, as high-fat meals have been shown to decrease its absorption. Therefore, ataluren should be taken with or without food, depending on the dosing regimen and the specific formulation. 

Distribution 

ataluren has moderate to high plasma protein binding, with approximately 75% to 90% bound to plasma proteins. It has a relatively large volume of distribution, indicating that it distributes widely throughout the body, but the exact tissue distribution and penetration into various organs are not well established. 

Metabolism 

ataluren is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C8, to form several metabolites. The metabolites of ataluren are primarily inactive, and the parent drug is the major circulating component in plasma. 

Elimination and Excretion 

ataluren is eliminated primarily through feces, with only a tiny proportion (less than 10%) excreted unchanged in the urine. The exact excretion mechanisms of ataluren and its metabolites are not fully understood, but it is believed to involve biliary excretion and subsequent fecal elimination. 

Adminstartion

Administration: 

• Dosage: The recommended dosage of ataluren may vary depending on the specific indication being treated. The typical dosage range for ataluren is 10 to 40 mg/kg/day, divided into two or three daily doses. The prescribing physician should determine the dosing regimen based on the patient’s weight, age, and clinical condition. 
• Oral administration: ataluren is administered orally as a tablet or as a powder for suspension. The tablets should be swallowed whole with water, and the powder for suspension should be mixed with a small amount of soft food or liquid, such as applesauce or yogurt, and taken immediately. 
• Food: ataluren can be taken with or without food, depending on the dosing regimen and the formulation. However, high-fat meals have decreased the absorption of ataluren, so following the specific dosing instructions provided by the prescribing physician or included in the product labeling is essential. 
• Compliance: It’s essential to take ataluren as the healthcare professional prescribes. Missing doses or not taking the medication as directed may affect its effectiveness. If a dose is missed, it should be taken as soon as possible unless it’s almost time for the next scheduled dose. Double dosing or extra doses of ataluren should be avoided without consulting a healthcare professional. 
• Duration of treatment: The duration of treatment with ataluren may vary depending on the specific indication and the patient’s response to the medication. It’s important to continue taking ataluren as the healthcare professional prescribes, even if there are no immediately noticeable effects. Only continuing ataluren with medical guidance can result in a loss of treatment benefits. 
• Special populations: The dosing and administration of ataluren may need to be adjusted in special populations, such as pediatric patients, geriatric patients, and patients with renal or hepatic impairment. The prescribing physician should determine the appropriate dosing regimen for these patients based on individual factors and clinical judgment. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ataluren 

Why do we use ataluren? 

ataluren is a medication approved to treat a specific genetic disorder called Duchenne muscular dystrophy (DMD) caused by a specific type of mutation known as nonsense. ataluren is indicated for treating DMD in patients with a confirmed nonsense mutation in the dystrophin gene who can walk independently. 

DMD is a rare and severe genetic disorder primarily affecting boys, causing progressive muscle weakness and wasting. Nonsense mutations are genetic mutations that lead to premature termination of protein synthesis, producing non-functional or truncated proteins. ataluren works by allowing the ribosome, the cellular machinery responsible for protein synthesis, to read through the premature stop codon caused by the nonsense mutation, thus allowing for the production of a full-length functional protein.