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| Clinical data | |
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| Trade names | Koselugo |
| Other names | AZD6244, ARRY-142886 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620030 |
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| Routes of administration | By mouth |
| Drug class | Protein kinase inhibitor |
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| Pharmacokinetic data | |
| Metabolism | Liver (probablyCYP3A4 andCYP2C19)[12] |
| Metabolites | N‐desmethyl‐selumetinib (active metabolite)[11] |
| Eliminationhalf-life | 5.3–7.2 hrs[11] |
| Excretion | Bile duct[11] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.169.311 |
| Chemical and physical data | |
| Formula | C17H15BrClFN4O3 |
| Molar mass | 457.68 g·mol−1 |
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Selumetinib (INN),[13] sold under the brand nameKoselugo, is amedication for the treatment of children, two years of age and older, withneurofibromatosis type I (NF-1), a genetic disorder of thenervous system causing tumors to grow on nerves.[14] It is takenby mouth.[8]
Common side effects include headache,abdominal pain and other problems of thegastrointestinal tract,fatigue, muscle pain, as well as dry skin and other skin problems.[8][14]
Selumetinib was approved for medical use in the United States in April 2020,[15] and in the European Union in June 2021.[9] The U.S.Food and Drug Administration (FDA) considers it to be afirst-in-class medication.[16]
Selumetinib is used for the treatment of neurofibromas in those withneurofibromatosis type I (NF-1).[17] This is a rare, progressive condition caused by a mutation or flaw in the gene coding for the proteinneurofibromin 1.[14] NF-1 is usually diagnosed in early childhood and appears in an estimated one out of every 3,000 infants.[14] It is characterized by changes in skin coloring (pigmentation),neurologic and skeletal impairments and risk for development ofbenign andmalignant tumors throughout life.[14]
It is approved specifically for children who have symptomatic, inoperableplexiform neurofibromas (PN), which are tumors involving thenerve sheaths (coating around nerve fibers) and can grow anywhere in the body, including the face, extremities, areas around the spine and deep in the body where they may affect organs. Between 30% and 50% of children born with NF-1 develop one or more PNs.[14]
Based on findings from animal studies, selumetinib may cause harm to a newborn baby when administered to a pregnant woman.[14] The FDA advises health care professionals to tell women of reproductive age, and men with female partners of reproductive potential, to use effectivecontraception during treatment with selumetinib, and for one week after the last dose.[14]
Common side effects are headache,nausea, vomiting,abdominal pain, diarrhea,fatigue,musculoskeletal pain (pain in the body affecting bones, muscles, ligaments, tendons and nerves), fever, dry skin,acneiform rash (acne) and otherrashes,stomatitis (inflammation of the mouth and lips),paronychia (infection in the skin that surrounds a toenail or fingernail) andpruritus (itching).[14]
Selumetinib can also cause serious side effects includingheart failure (manifested as ejection fraction decrease, or when the muscle of the left ventricle of the heart is not pumping as well as normal) andeyetoxicity (acute and chronic damage to the eye) includingretinal vein occlusion,retinal pigment epithelial detachment and impaired vision.[14] Selumetinib can also cause increasedcreatinine phosphokinase (CPK).[14] CPK is an enzyme found in the heart, brain and skeletal muscles.[14] When muscle tissue is damaged, CPK leaks into a person's blood, which can be a sign ofrhabdomyolysis (breakdown of skeletal muscle due to direct or indirect muscle injury).[14] Further, selumetinib capsules containvitamin E, and users are at an increased risk of bleeding if their daily intake of vitamin E exceeds the recommended or safe limits.[14]
As selumetinib is thought to be metabolized by the liver enzymesCYP3A4 andCYP2C19,[12] use of moderate to strong CYP3A4inhibitors (such asgrapefruit juice) and of the CYP2C19 inhibitorfluconazole is discouraged for people taking selumetinib.[18]
Selumetinib is akinase inhibitor, more specifically a selective inhibitor of the enzymemitogen-activated protein kinase kinase (MAPK kinase or MEK) subtypes1 and2. These enzymes are part of theMAPK/ERK pathway, which regulatescell proliferation (i.e., growth and division) and is overly active in many types of cancer.[18]
Selumetinib was discovered byArray BioPharma and was licensed toAstraZeneca.[citation needed] It has been investigated for the treatment of various types of cancer, such asnon-small cell lung cancer (NSCLC) andthyroid cancer.[19][20]
The USFood and Drug Administration (FDA) granted the application for selumetinibpriority review,breakthrough therapy, andorphan drug designations.[14] It was granted a rare pediatric disease designation for the treatment of pediatric NF-1 along with a rare pediatric disease priority review voucher.[14] In April 2020, selumetinib was approved by the FDA for the treatment of children with NF-1.[21][22][15] It is the first drug approved in the US to treat this rare disease.[14]
The approval was based on a clinical trial[23] of children who had NF-1 and inoperable plexiform neurofibromas (defined as a PN that could not be completely removed without risk for substantial morbidity to the child), conducted by theNational Cancer Institute.[14][22] Theefficacy results were from 50 of the children who received the recommended dose and had routine evaluations of changes in tumor size and tumor-related morbidities during the trial.[14] The children received selumetinib 25 mg/m2 orally twice a day until disease progression or until they experienced unacceptable adverse reactions.[14][22] The clinical trial measured theoverall response rate (ORR), defined as the percentage of subjects with a complete response and those who experienced more than a 20% reduction in PN volume onMRI that was confirmed on a subsequent MRI within 3 to 6 months.[14] The ORR was 66% and all subjects had a partial response, meaning that no subjects had complete disappearance of the tumor.[14] Of these subjects, 82% had a response lasting 12 months or longer.[14] The trial was conducted at four sites in the United States.[22]
Other clinical outcomes for subjects during selumetinib treatment included changes in PN-related disfigurement, symptoms and functional impairments.[14] Although the sample sizes of subjects assessed for each PN-related morbidity (such as disfigurement, pain, strength and mobility problems, airway compression, visual impairment and bladder or bowel dysfunction) were small, there appeared to be a trend of improvement in PN-related symptoms or functional deficits during treatment.[14]
Selumetinib has also been shown to inhibit growth ofGNAQ mutated uveal melanoma cell lines.[24] Furthermore, preliminary results suggest that selumetinib treatment of uveal melanoma patients can result in tumor shrinkage as the consequence of sustained inhibition ofERKphosphorylation.[25]
APhase II clinical trial about selumetinib in NSCLC was completed in September 2011;[26] one about cancers withBRAF mutations is ongoing as of June 2012[update].[27]
In July 2015, selumetinib failed a Phase III trial testing whether the drug significantly prolonged the survival of patients in a study onmelanoma originating in the eye. In the 152-patient trial, a combination of selumetinib anddacarbazine failed to improveprogression-free survival compared with just the old drug alone.[28][29]
As of March 2016[update], there were other phase III trials registered for thyroid cancer,[30] andKRAS positive NSCLC.[31] The combination of selumetinib to chemotherapy improved median progression-free survival in a trial of 510 patients with advancedKRAS-mutant NSCLC just for one month, which was statistically not significant.[32]
In November 2018, investigators working withnasal polyp tissuein vitro demonstrated a synergistic effect of down regulating expression of p-MEK1 and p-ERK1 when it was administered witherythromycin.[33]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.
