Selumetinib Explained

Verifiedrevid:416014858
Tradename:Koselugo
Dailymedid:Selumetinib
Pregnancy Au:D
Pregnancy Au Comment:[1]
Pregnancy Category:Contraindicated
Routes Of Administration:By mouth
Class:Protein kinase inhibitor
Atc Prefix:L01
Atc Suffix:EE04
Legal Au:S4
Legal Au Comment:[2] [3] [4]
Legal Ca:Rx-only
Legal Ca Comment:[5] [6] [7]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[8] [9]
Metabolism:Liver (probably CYP3A4 and CYP2C19)
Metabolites:N‐desmethyl‐selumetinib (active metabolite)[10]
Elimination Half-Life:5.3–7.2 hrs
Excretion:Bile duct
Index2 Label:as salt
Cas Number:606143-52-6
Cas Number2:943332-08-9
Pubchem:10127622
Drugbank:DB11689
Drugbank2:DBSALT002048
Chemspiderid:8303141
Chemspiderid2:17342538
Unii:6UH91I579U
Unii2:807ME4B7IJ
Kegg:D09666
Kegg2:D10024
Chebi:90227
Chembl:1614701
Chembl2:2105684
Pdb Ligand:3EW
Synonyms:AZD6244, ARRY-142886
Iupac Name:6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide
C:17
H:15
Br:1
Cl:1
F:1
N:4
O:3
Smiles:CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)Cl)C(=O)NOCCO
Stdinchi:1S/C17H15BrClFN4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)
Stdinchikey:CYOHGALHFOKKQC-UHFFFAOYSA-N

Selumetinib (),[11] sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves.[12] It is taken by mouth.[13]

Common side effects include headache, abdominal pain and other problems of the gastrointestinal tract, fatigue, muscle pain, as well as dry skin and other skin problems.

Selumetinib was approved for medical use in the United States in April 2020, and in the European Union in June 2021. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[14]

Medical uses

Selumetinib is used for the treatment of neurofibromas in those with neurofibromatosis type I (NF-1).[15] This is a rare, progressive condition caused by a mutation or flaw in the gene coding for the protein neurofibromin 1. NF-1 is usually diagnosed in early childhood and appears in an estimated one out of every 3,000 infants. It is characterized by changes in skin coloring (pigmentation), neurologic and skeletal impairments and risk for development of benign and malignant tumors throughout life.

It is approved specifically for children who have symptomatic, inoperable plexiform neurofibromas (PN), which are tumors involving the nerve 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.

Pregnancy

Based on findings from animal studies, selumetinib may cause harm to a newborn baby when administered to a pregnant woman. The FDA advises health care professionals to tell women of reproductive age, and men with female partners of reproductive potential, to use effective contraception during treatment with selumetinib, and for one week after the last dose.

Adverse effects

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 other rashes, stomatitis (inflammation of the mouth and lips), paronychia (infection in the skin that surrounds a toenail or fingernail) and pruritus (itching).

Selumetinib can also cause serious side effects including heart failure (manifested as ejection fraction decrease, or when the muscle of the left ventricle of the heart is not pumping as well as normal) and eye toxicity (acute and chronic damage to the eye) including retinal vein occlusion, retinal pigment epithelial detachment and impaired vision. Selumetinib can also cause increased creatinine phosphokinase (CPK). CPK is an enzyme found in the heart, brain and skeletal muscles. When muscle tissue is damaged, CPK leaks into a person's blood, which can be a sign of rhabdomyolysis (breakdown of skeletal muscle due to direct or indirect muscle injury). Further, selumetinib capsules contain vitamin E, and users are at an increased risk of bleeding if their daily intake of vitamin E exceeds the recommended or safe limits.

Interactions

As selumetinib is thought to be metabolized by the liver enzymes CYP3A4 and CYP2C19,[16] use of moderate to strong CYP3A4 inhibitors (such as grapefruit juice) and of the CYP2C19 inhibitor fluconazole is discouraged for people taking selumetinib.

Pharmacology

Mechanism of action

Selumetinib is a kinase inhibitor, more specifically a selective inhibitor of the enzyme mitogen-activated protein kinase kinase (MAPK kinase or MEK) subtypes 1 and 2. These enzymes are part of the MAPK/ERK pathway, which regulates cell proliferation (i.e., growth and division) and is overly active in many types of cancer.[17]

History

Selumetinib was discovered by Array BioPharma and was licensed to AstraZeneca. It has been investigated for the treatment of various types of cancer, such as non-small cell lung cancer (NSCLC) and thyroid cancer.[18] [19]

The US Food and Drug Administration (FDA) granted the application for selumetinib priority review, breakthrough therapy, and orphan drug designations. It was granted a rare pediatric disease designation for the treatment of pediatric NF-1 along with a rare pediatric disease priority review voucher. In April 2020, selumetinib was approved by the FDA for the treatment of children with NF-1.[20] [21] [22] It is the first drug approved in the US to treat this rare disease.

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 the National Cancer Institute. The efficacy 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. The children received selumetinib 25 mg/m2 orally twice a day until disease progression or until they experienced unacceptable adverse reactions. The clinical trial measured the overall 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 on MRI that was confirmed on a subsequent MRI within 3 to 6 months. The ORR was 66% and all subjects had a partial response, meaning that no subjects had complete disappearance of the tumor. Of these subjects, 82% had a response lasting 12 months or longer. The trial was conducted at four sites in the United States.

Other clinical outcomes for subjects during selumetinib treatment included changes in PN-related disfigurement, symptoms and functional impairments. 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.

Research

Selumetinib has also been shown to inhibit growth of GNAQ 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 of ERK phosphorylation.[25]

A Phase II clinical trial about selumetinib in NSCLC was completed in September 2011;[26] one about cancers with BRAF mutations is ongoing .[27]

In July 2015, selumetinib failed a Phase III trial testing whether the drug significantly prolonged the survival of patients in a study on melanoma originating in the eye. In the 152-patient trial, a combination of selumetinib and dacarbazine failed to improve progression-free survival compared with just the old drug alone.[28] [29]

, there were other phase III trials registered for thyroid cancer,[30] and KRAS positive NSCLC.[31] The combination of selumetinib to chemotherapy improved median progression-free survival in a trial of 510 patients with advanced KRAS-mutant NSCLC just for one month, which was statistically not significant.[32]

In November 2018, investigators working with nasal polyp tissue in vitro demonstrated a synergistic effect of down regulating expression of p-MEK1 and p-ERK1 when it was administered with erythromycin.[33]

Further reading

External links

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023.
  2. Web site: Koselugo . Therapeutic Goods Administration (TGA) . 15 December 2021 . 27 December 2021 . 28 December 2021 . https://web.archive.org/web/20211228080410/https://www.tga.gov.au/apm-summary/koselugo . live .
  3. Web site: Australian Government Department of Health Therapeutic Goods Administration Public Summary KOSELUGO selumetinib 10 mg capsule bottle . https://web.archive.org/web/20220613065401/https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs%2FPublicHTML%2FpdfStore.nsf&docid=0D6160A0F721AD95CA25879F003CAC27&agid=%28PrintDetailsPublic%29&actionid=1 . 13 June 2022.
  4. Web site: AusPAR: Selumetinib . Therapeutic Goods Administration (TGA) . 31 May 2022 . 13 June 2022 . 31 May 2022 . https://web.archive.org/web/20220531202819/http://www.tga.gov.au/auspar/auspar-selumetinib . live .
  5. Web site: Koselugo Product information . . 25 April 2012 . 30 September 2022 .
  6. Web site: Summary Basis of Decision - Koselugo . . 24 January 2023 . 24 January 2023 . https://web.archive.org/web/20230124031805/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00615&lang=en . dead .
  7. Web site: Details for: Koselugo . . 6 September 2023 . 3 March 2024.
  8. Web site: Koselugo EPAR . European Medicines Agency . 20 April 2021 . 4 March 2023.
  9. Web site: Koselugo Product information . Union Register of medicinal products . 3 March 2023.
  10. 28326681. Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas . May 2017 . Patel YT, Daryani VM, Patel P, Zhou D, Fangusaro J, Carlile DJ, Martin PD, Aarons L, Stewart CF . 6 . CPT: Pharmacometrics & Systems Pharmacology . 6 . 5 . 305–314 . 10.1002/psp4.12175 . 5445231 .
  11. ((World Health Organization)). International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 62. WHO Drug Information. 2009. 261. 23. 3. 10665/74420. free.
  12. FDA Approves First Therapy for Children with Debilitating and Disfiguring Rare Disease . U.S. Food and Drug Administration (FDA) . 10 April 2020 . 10 April 2020 . 10 April 2020 . https://web.archive.org/web/20200410195741/https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-children-debilitating-and-disfiguring-rare-disease . live .
  13. Web site: Koselugo- selumetinib capsule . DailyMed . 10 April 2020 . 18 April 2020 . 18 April 2020 . https://web.archive.org/web/20200418205350/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7d042c61-f28f-4ab5-ab10-d7558c0d49ff . live .
  14. Web site: New Drug Therapy Approvals 2020 . U.S. Food and Drug Administration (FDA) . 31 December 2020 . 17 January 2021 . 18 January 2021 . https://web.archive.org/web/20210118011953/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020 . live .
  15. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC . 6 . Selumetinib in Children with Inoperable Plexiform Neurofibromas . New England Journal of Medicine . April 2020 . 382 . 15 . 1430–1442 . 10.1056/nejmoa1912735. 32187457 . 7305659 .
  16. 10.1016/j.clinthera.2016.09.002. Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. November 2016 . Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P . 6 . Clinical Therapeutics. 38. 11. 2447–2458. 27751676. free . doi .
  17. Selumetinib . Accessed 14 April 2021.
  18. News: Array BioPharma strikes rights deal with Japanese firm worth up to $76M-plus. 31 March 2016. BizWest. 12 June 2018. 12 June 2018. https://web.archive.org/web/20180612184709/https://bizwest.com/2016/03/31/array-biopharma-strikes-rights-deal-japanese-firm-worth-76m/. live.
  19. Casaluce F, Sgambato A, Maione P, Sacco PC, Santabarbara G, Gridelli C . Selumetinib for the treatment of non-small cell lung cancer . Expert Opinion on Investigational Drugs . 26 . 8 . 973–84 . August 2017 . 28675058 . 10.1080/13543784.2017.1351543 . 40860991 .
  20. Web site: Selumetinib: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 10 April 2020 . 18 January 2021 . https://web.archive.org/web/20210118020002/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=213756 . live .
  21. Web site: Drug Trials Snapshots: Koselugo . U.S. Food and Drug Administration (FDA) . 10 April 2020 . 18 April 2020 . 18 April 2020 . https://web.archive.org/web/20200418205151/https://www.fda.gov/drugs/resources-information-approved-drugs/drug-trials-snapshots-koselugo . live .
  22. Web site: Drug Approval Package: Koselugo . U.S. Food and Drug Administration (FDA) . 11 May 2020 . 18 January 2021 . 22 January 2021 . https://web.archive.org/web/20210122053817/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000TOC.cfm . live .
  23. . Accessed 14 April 2021.
  24. Ambrosini G, Pratilas CA, Qin LX, Tadi M, Surriga O, Carvajal RD, Schwartz GK . Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance . Clinical Cancer Research . 18 . 13 . 3552–61 . July 2012 . 22550165 . 3433236 . 10.1158/1078-0432.CCR-11-3086 .
  25. News: Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma . 2012 . 10 June 2014 . 29 August 2021 . https://web.archive.org/web/20210829170821/https://meetinglibrary.asco.org/record/70605/abstract . live .
  26. AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients . ClinicalTrials.gov . 30 April 2009 . 10 April 2020 . 11 April 2020 . https://web.archive.org/web/20200411011920/https://clinicaltrials.gov/ct2/show/NCT00890825 . live .
  27. Selumetinib in Cancers With BRAF Mutations . ClinicalTrials.gov . 27 April 2009 . 10 April 2020 . 11 April 2020 . https://web.archive.org/web/20200411011922/https://clinicaltrials.gov/ct2/show/NCT00888134 . live .
  28. AstraZeneca provides update on selumetinib in uveal melanoma . AstraZeneca . 22 July 2015 . 10 April 2020 . 11 April 2020 . https://web.archive.org/web/20200411011926/https://www.astrazeneca.com/media-centre/press-releases/2015/astrazeneca-selumetinib-uveal-melanoma-oncology-22072015.html . live .
  29. Web site: AstraZeneca's once-lauded drug flunks a Phase III eye cancer trial. FierceBiotech. 22 July 2015 . 22 July 2015. 4 March 2016. https://web.archive.org/web/20160304112824/http://www.fiercebiotech.com/story/astrazenecas-once-lauded-drug-flunks-phase-iii-eye-cancer-trial/2015-07-22. live.
  30. Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patient With Differentiated Thyroid Cancer (ASTRA) . ClinicalTrials.gov . 30 April 2013 . 10 April 2020 . 11 April 2020 . https://web.archive.org/web/20200411011921/https://clinicaltrials.gov/ct2/show/NCT01843062 . live .
  31. Web site: Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1) . ClinicalTrials.gov . 2 September 2013 . 10 April 2020 . 11 April 2020 . https://web.archive.org/web/20200411011928/https://clinicaltrials.gov/ct2/show/NCT01933932 . live .
  32. Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, Orlov S, Blackhall F, Wolf J, Garrido P, Poltoratskiy A, Mariani G, Ghiorghiu D, Kilgour E, Smith P, Kohlmann A, Carlile DJ, Lawrence D, Bowen K, Vansteenkiste J . 6 . Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial . JAMA . 317 . 18 . 1844–53 . May 2017 . 28492898 . 5815037 . 10.1001/jama.2017.3438 .
  33. 30414267. November 2018. Liu X, Wang X, Chen L, Shi Y, Wei Y . Effects of Erythromycin on the Proliferation and Apoptosis of Cultured Nasal Polyp-Derived Cells and the Extracellular Signal-Regulated Kinase (ERK)/Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway. Medical Science Monitor. 24. 8048–8055. 10.12659/MSM.910934 . 6240169 .

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