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General Description:

Eteplirsen, identified by CAS number 1173755-55-9, is a notable compound with significant therapeutic applications. Eteplirsen is a synthetic antisense oligonucleotide and a phosphorodiamidate morpholino oligomer. It consists of a six-membered morpholino ring replacing the five-membered ribofuranosyl rings found in natural DNA and RNA. Duchenne muscular dystrophy is a rare genetic disorder characterized by progressive muscle deterioration and premature death most commonly due to respiratory or cardiac complications. It is caused by loss-of-function mutations in the DMD gene coding for dystrophin, an essential protein involved in maintaining the structural integrity and function of muscle fibres. Eteplirsen was first approved by the FDA in September 2016 for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene, which codes for dystrophin, that is amenable to exon 51 skipping. Eteplirsen directly works on the DMD gene to promote dystrophin production. Eteplirsen was the first treatment for DMD approved by the FDA.

Indications:

This drug is primarily indicated for: Eteplirsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Eteplirsen undergoes metabolic processing primarily in: Eteplirsen does not undergo hepatic metabolism. As with other phosphorodiamidate morpholino oligomers, it is not favorable to metabolism. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Eteplirsen are crucial for its therapeutic efficacy: Following single or multiple intravenous infusions, the peak plasma concentrations (C_max) of eteplirsen occurred near the end of infusion (i.e, 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week). The inter-subject variability for eteplirsen C_max and AUC range from 20 to 55%. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Eteplirsen is an important consideration for its dosing schedule: The elimination half-life (t1/2) of eteplirsen was three to four hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Eteplirsen exhibits a strong affinity for binding with plasma proteins: _In vitro_, eteplirsen is 6 to 17% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Eteplirsen from the body primarily occurs through: Renal clearance of eteplirsen accounts for approximately 67-70% of the administered dose within 24 hours of intravenous administration. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Eteplirsen is distributed throughout the body with a volume of distribution of: Following weekly intravenous infusion of eteplirsen at 30 mg/kg, the mean apparent volume of distribution (Vss) was 600 mL/kg. No accumulation is seen with once-weekly dosing. Eteplirsen is not widely distributed. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Eteplirsen is a critical factor in determining its safe and effective dosage: The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Eteplirsen exerts its therapeutic effects through: Eteplirsen is a disease-modifying agent that aims to slow down the progression of Duchenne muscular dystrophy (DMD), but does not cure the disease itself. While it is unclear how to properly estimate dystrophin production in muscle tissue in clinical studies, eteplirsen increases the levels of dystrophin protein in patients with DMD. Patients treated with eteplirsen produce mRNA for a truncated dystrophin protein. Internally truncated dystrophin protein is often found in patients with Becker muscular dystrophy, a less severe form of dystrophinopathy caused by defective DMD gene variants leading to in-frame mutations and production of functional, truncated versions of dystrophin. Eteplirsen aims to render the disease less severe and attenuate the rate of functional decline. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Eteplirsen functions by: Dystrophin is a membrane-associated protein that links cytoskeletal actin in muscle fibres with the surrounding extracellular matrix by forming a network with sarcolemmal glycoproteins. This linkage strengthens muscle structure during stressful contraction and relaxation cycles. The loss of dystrophin leads to mechanical damage of muscle fibres and eventually muscle degeneration. Duchenne muscular dystrophy (DMD) is caused by deletion mutations in exons 43 to 55 of the DMD gene coding for dystrophin, which is the largest known human gene. These mutations disrupt the open reading frame and cease the normal production of dystrophin. About 60% of DMD cases are caused by deletions of at least one exon in DMD and about 13-14% of patients with DMD have exon 51 amenable deletions. Deletions ending at exon 50 and starting at exon 52 represents the largest group of patients to which single exon skipping is applicable. Eteplirsen mediates its effect by inducing exon skipping in defective gene variants. Eteplirsen selectively binds to exon 51 of dystrophin pre-mRNA, excluding this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Through exon skipping, eteplirsen restores the open reading frame of the DMD gene and allows the production of functional dystrophin. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Eteplirsen is categorized under the following therapeutic classes: Antisense Oligonucleotides, Morpholines, Musculo-Skeletal System, Nucleic Acids, Nucleotides, and Nucleosides, Nucleotides, Oligonucleotides, Oxazines, Polynucleotides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Eteplirsen include:

• Molecular Weight: 10305.0
• Molecular Formula: C364H569N177O122P30