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General Description:

Golodirsen, identified by CAS number 1422959-91-8, is a notable compound with significant therapeutic applications. Golodirsen is a morpholino antisense oligomer designed to treat about 8% of patients with Duchenne Muscular Dystrophy (DMD). This is an X-linked condition leading to progressive muscle degeneration that begins in early childhood, rendering many patients wheelchair-bound by age 12. Often, patients succumb to this condition by age 30 or younger due to cardiac and respiratory complications. A similar drug used in the treatment of other types of DMD is , which targets a different genetic mutation. Golodirsen was developed by Sarepta Therapeutics and granted accelerated FDA approval on December 12, 2019 due to the urgent need for this drug in patients suffering from a certain form of DMD. Continued approval of this drug will depend on the results of clinical trials that confirm its clinical benefit. Golodirsen was initially rejected for FDA approval over concerns about its potential renal toxicity, however, clinical trials did not show significant toxicity.

Indications:

This drug is primarily indicated for: Golodirsen is indicated to treat Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that would benefit from exon 53 skipping. Continued FDA approval of this drug is contingent upon the results of clinical trials to confirm its benefit. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Golodirsen undergoes metabolic processing primarily in: Golodirsen is not extensively metabolized. There were no metabolites detected in plasma or urine during a pharmacokinetic study. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Golodirsen are crucial for its therapeutic efficacy: This drug is given by the intravenous route, and is likely rapidly absorbed into the circulation. Pharmacokinetic studies for eteplirsen determined that Cmax occur within 1.1 to 1.2 hours of infusion initiation, after the administration of doses ranging from 0.5 mg/kg/week to 50 mg/kg/week. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Golodirsen is an important consideration for its dosing schedule: In a pharmacokinetic study, the elimination half-life of golodirsen was 3.4 hours with a standard deviation of 0.6 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Golodirsen exhibits a strong affinity for binding with plasma proteins: The protein binding of golodirsen ranges from 33 to 39%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Golodirsen from the body primarily occurs through: Golodirsen is excreted primarily as unchanged drug in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Golodirsen is distributed throughout the body with a volume of distribution of: The volume of distribution at steady-state is approximately 668 mL/kg at 30 mL/kg dose of golodirsen. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Golodirsen is a critical factor in determining its safe and effective dosage: This drug is rapidly cleared from the systemic circulation, like other members of its drug class. The total clearance of eteplirsen, a drug from the same class, was 339 mL/h/kg after regular doses of 30 mg/kg/week. The clearance of golodirsen is likely similar. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Golodirsen exerts its therapeutic effects through: Golodirsen masks genetic mutations that result in a cascade of events which treat Duchenne Muscular Dystrophy in about 8% of patients. Golodirsen indirectly induces the production of dystrophin, an important protein for muscle function. It is not yet confirmed whether motor function is improved by golodirsen, however, clinical trials are underway to examine its clinical benefits. A note on nephrotoxicity Though clinical trials have not yet confirmed that golodirsen is nephrotoxic, other morpholino antisense oligonucleotides have been known to cause nephrotoxicity. Ensure to monitor renal function during golodirsen therapy. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Golodirsen functions by: The hallmark of Duchenne Muscular Dystrophy is the absence of the important muscle stabilizing protein, dystrophin, that is caused by a deletion mutation on the DMD (dystrophin) gene. This results in the production of a non-functional protein. Lack of dystrophin protein leads to progressive muscle weakness and degeneration. Golodirsen binds to exon 53 of dystrophin pre-mRNA on the DMD gene, excluding this protein coding unit during mRNA processing. The exclusion (or skipping) of exon 53 by golodirsen has the end result of changing out-of-frame mRNA to in-frame mRNA, inducing the production of dystrophin. The production of an imperfect dystrophin protein induced by golodirsen likely leads to a less severe condition, Becker Muscular Dystrophy (BMD), characterized by the production of a truncated dystrophin protein. Patients with BMD generally can expect a longer lifespan and improved quality of life. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Golodirsen is categorized under the following therapeutic classes: Antisense Elements (Genetics), Antisense Oligonucleotides, Compounds used in a research, industrial, or household setting, Drugs that are Mainly Renally Excreted, Laboratory Chemicals, Molecular Probes, Musculo-Skeletal System, Nucleic Acid Probes, Nucleic Acids, Nucleic Acids, Nucleotides, and Nucleosides, Nucleotides, Oligonucleotides, Polynucleotides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.