Selumetinib

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Signal Transduction Inhibitors; MEK Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

Danger

H302 (40%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P264+P265, P270, P272, P273, P280, P301+P317, P302+P352, P305+P354+P338, P317, P318, P319, P321, P330, P333+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In the prelicensure clinical trials conducted in children and adults with neurofibromatosis, serum aminotransferase elevations occurred in 35% of treated subject but rose to above 5 times the upper limit of normal (ULN) in only 4%. However, there were no liver related serious adverse events and no patient had a concurrent elevation in serum aminotransferase and bilirubin levels. The ALT elevations were typically mild and transient and usually resolved even without dose adjustment. There were no instances of clinically apparent liver injury attributed to selumetinib. Since approval and more wide scale availability of selumetinib, there have been no published reports of clinically apparent drug induced liver injury associated with its use in neurofibromatosis, although clinical experience with the drug, particularly with long term therapy, has been limited. However, in studies of experimental therapy with somewhat higher doses of selumetinib in patients with advanced, refractory cancers, liver test abnormalities were common and sometimes graded as severe (ALT above 20 times ULN) and requiring drug discontinuation. Thus, in patients with neurofibromatosis and use of recommended doses of selumetinib, clinically apparent liver injury is rare if it occurs at all. At higher doses, however, selumetinib has been associated with a very high rate of serum enzyme elevations, many of which were in the range suggestive of severe injury.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

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 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.

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.

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.

6UH91I579U

SELUMETINIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Mitogen-Activated Protein Kinase Kinase 1 Inhibitors

Mechanisms of Action [MoA] - Mitogen-Activated Protein Kinase Kinase 2 Inhibitors

Selumetinib is a Kinase Inhibitor. The mechanism of action of selumetinib is as a Mitogen-Activated Protein Kinase Kinase 1 Inhibitor and Mitogen-Activated Protein Kinase Kinase 2 Inhibitor.

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.

Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine.

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.

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.