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General Description:

Selumetinib, identified by CAS number 606143-52-6, is a notable compound with significant therapeutic applications. Activation of the Raf-MEK-ERK signaling pathway is known to be implemented in several types of malignancies, thus, mitogen-activated protein kinase kinase (MEK) inhibitors such as selumetinib are important tools that can target the problematic overactivity of this pathway. Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming. However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumors in Phase II trials. Currently, the novel MEK 1 / 2 inhibitor, selumetinib, is approved solely for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group. NF-1 is considered rare with an estimated incidence of 1/3000 individuals. It is a genetic, autosomal dominant condition resulting from mutations of the NF1 gene, which can lead to various complications including the development of multiple tumors in the nervous system. Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered to be relatively uncommon compared to other variants of NF-1. Luckily, the use of selumetinib in patients with NF-1 has shown efficacy in shrinking associated tumors and is linked to other positive clinical outcomes.

Indications:

This drug is primarily indicated for: Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Selumetinib undergoes metabolic processing primarily in: Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows : Hydrolysis of selumetinib’s amide functional group produces M15 (AZ13326637), which contains a carboxylic acid. Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite. Amide hydrolysis transforms M14 into M15, glucuronidation and further oxidation of M14 leads to M2, M6 and M1, and N-demethylation of M14 produces M12. The amide glucuronide (M2) is thought to be the major circulating metabolite. Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11. Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12. Although the N-demethylated metabolite (M8) accounts for <10% of the circulating metabolites, it is responsible for approximately 21-35% of any observed pharmacological activity. Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites. Glucuronidation of M10 produces M1. Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Selumetinib are crucial for its therapeutic efficacy: Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1.5 hours. In healthy adults, the mean absolute oral bioavailability was reported to be 62%. Selumetinib should be administered on an empty stomach since food significantly decreases serum concentrations of the drug. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Selumetinib is an important consideration for its dosing schedule: Selumetinib is characterized by a short half-life. The elimination half-life associated with a dose of 25 mg/m² in pediatric patients is 6.2 hours. In a study observing the pharmacokinetic effects of various selumetinib regimens in select Japanese patients, the half-life ranged from 9.2- 10.6 hours. In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Selumetinib exhibits a strong affinity for binding with plasma proteins: Separate studies investigating selumetinib protein binding found that 96% of selumetinib was bound to serum albumin, while <35% was bound to ɑ-1 acid glycoprotein. Overall, approximately 98.4% of selumetinib is plasma protein bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Selumetinib from the body primarily occurs through: Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Selumetinib is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L. A study in healthy adult males found a mean apparent volume of distribution of 146 L. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found that the apparent volume of distribution values at steady-state ranged from 73.2 - 148.1 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Selumetinib is a critical factor in determining its safe and effective dosage: The clearance of selumetinib in pediatric patients is 8.8 L/hr. A study in healthy adult males found a clearance value of 15.7 L/hr. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found clearance values that ranged from 9.2 - 15.9 L/hr. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Selumetinib exerts its therapeutic effects through: Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Selumetinib functions by: The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Selumetinib belongs to the class of organic compounds known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds), classified under the direct parent group Benzimidazoles. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Benzimidazoles class, specifically within the None subclass.

Categories:

Selumetinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2E1 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Kinase Inhibitor, Mitogen-activated protein kinase (MEK) inhibitors, Mitogen-Activated Protein Kinase Kinase 1 Inhibitors, Mitogen-Activated Protein Kinase Kinase 2 Inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Tyrosine Kinase Inhibitors, UGT1A1 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.