Peringatan Keamanan

Toxicity information regarding selumetinib is not readily available. Patients experiencing an overdose are at an increased risk of adverse effects such as cardiomyopathy, ocular toxicity, and diarrhea. It is generally thought that since selumetinib is extensively protein-bound, dialysis is unlikely to be helpful in situations of overdose.A193713,L12852

Selumetinib

DB11689

small molecule approved investigational

Deskripsi

Activation of the Raf-MEK-ERK signalling 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.A193611
Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming.A193611 However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumours in Phase II trials.A193611

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.A193608 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 tumours in the nervous system.A193533,A193608 Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered relatively uncommon compared to other variants of NF-1.A193608 Luckily, the use of selumetinib in patients with NF-1 have shown efficacy in shrinking associated tumours and is linked to other positive clinical outcomes.A193533 Selumetinib was approved by the FDA on April 10, 2020.L49991 It was later approved by Health Canada on August 23, 2022.L49986

Struktur Molekul 2D

Berat 457.68
Wujud -

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Selumetinib is characterized by a short half-life.[A193536] The elimination half-life associated with a dose of 25 mg/m<sup>2</sup> in pediatric patients is 6.2 hours.[L12852] 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.[A193536] In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours.[A193422]
Volume Distribusi The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L.[L12852] A study in healthy adult males found a mean apparent volume of distribution of 146 L.[A193422] 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.[A193536]
Klirens (Clearance) The clearance of selumetinib in pediatric patients is 8.8 L/hr.[L12852] A study in healthy adult males found a clearance value of 15.7 L/hr.[A193422] 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.[A193536]

Absorpsi

Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1.5 hours.A193536,A193422,L12852 In healthy adults, the mean absolute oral bioavailability was reported to be 62%.L12852 Selumetinib should be administered on an empty stomach since food significantly decreases serum concentrations of the drug.L12852

Metabolisme

Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows A193422: Hydrolysis of selumetinib’s amide functional group produces M15 (AZ13326637), which contains a carboxylic acid.A193422 Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite.A193422 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.A193422 The amide glucuronide (M2) is thought to be the major circulating metabolite.A193422 Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11.A193422 Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12.A193422 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.A193422,L12852 Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites.A193422 Glucuronidation of M10 produces M1.A193422 Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites.A193422

Rute Eliminasi

Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine.A193422,L12852

Interaksi Makanan

1 Data
  • 1. Take on an empty stomach. Avoid consuming food 2 hours before and 1 hour after each dose.

Interaksi Obat

993 Data
Ranolazine The serum concentration of Selumetinib can be increased when it is combined with Ranolazine.
Deferasirox The serum concentration of Selumetinib can be increased when it is combined with Deferasirox.
Peginterferon alfa-2b The serum concentration of Selumetinib can be increased when it is combined with Peginterferon alfa-2b.
Leflunomide The serum concentration of Selumetinib can be decreased when it is combined with Leflunomide.
Teriflunomide The serum concentration of Selumetinib can be decreased when it is combined with Teriflunomide.
Dabrafenib The serum concentration of Selumetinib can be decreased when it is combined with Dabrafenib.
Mifepristone The serum concentration of Selumetinib can be increased when it is combined with Mifepristone.
Desogestrel The metabolism of Selumetinib can be increased when combined with Desogestrel.
Zidovudine The metabolism of Selumetinib can be increased when combined with Zidovudine.
Lamotrigine The metabolism of Selumetinib can be increased when combined with Lamotrigine.
Ethinylestradiol The metabolism of Selumetinib can be increased when combined with Ethinylestradiol.
Testosterone propionate The metabolism of Selumetinib can be increased when combined with Testosterone propionate.
Cyproterone acetate The metabolism of Selumetinib can be increased when combined with Cyproterone acetate.
Albendazole The metabolism of Selumetinib can be increased when combined with Albendazole.
Caffeine The metabolism of Selumetinib can be decreased when combined with Caffeine.
Moxifloxacin The metabolism of Selumetinib can be decreased when combined with Moxifloxacin.
Lidocaine The risk or severity of methemoglobinemia can be increased when Selumetinib is combined with Lidocaine.
Mexiletine The metabolism of Selumetinib can be decreased when combined with Mexiletine.
Alosetron The metabolism of Selumetinib can be decreased when combined with Alosetron.
Gatifloxacin The metabolism of Selumetinib can be decreased when combined with Gatifloxacin.
Dosulepin The metabolism of Selumetinib can be decreased when combined with Dosulepin.
Lobeglitazone The metabolism of Selumetinib can be decreased when combined with Lobeglitazone.
Pazufloxacin The metabolism of Selumetinib can be decreased when combined with Pazufloxacin.
Osilodrostat The metabolism of Selumetinib can be decreased when combined with Osilodrostat.
Imipramine The metabolism of Selumetinib can be decreased when combined with Imipramine.
Ticlopidine The metabolism of Selumetinib can be decreased when combined with Ticlopidine.
Chloramphenicol The metabolism of Selumetinib can be decreased when combined with Chloramphenicol.
Lansoprazole The metabolism of Selumetinib can be decreased when combined with Lansoprazole.
Fluoxetine The metabolism of Selumetinib can be decreased when combined with Fluoxetine.
Zafirlukast The metabolism of Selumetinib can be decreased when combined with Zafirlukast.
Gemfibrozil The metabolism of Selumetinib can be decreased when combined with Gemfibrozil.
Clomipramine The metabolism of Selumetinib can be decreased when combined with Clomipramine.
Eslicarbazepine acetate The metabolism of Selumetinib can be decreased when combined with Eslicarbazepine acetate.
Troglitazone The metabolism of Selumetinib can be decreased when combined with Troglitazone.
Nabilone The metabolism of Selumetinib can be decreased when combined with Nabilone.
Imatinib The metabolism of Selumetinib can be decreased when combined with Imatinib.
Felbamate The metabolism of Selumetinib can be decreased when combined with Felbamate.
Sulfinpyrazone The metabolism of Selumetinib can be decreased when combined with Sulfinpyrazone.
Iproniazid The metabolism of Selumetinib can be decreased when combined with Iproniazid.
Medical Cannabis The metabolism of Selumetinib can be decreased when combined with Medical Cannabis.
Valproic acid The metabolism of Selumetinib can be decreased when combined with Valproic acid.
Floxuridine The metabolism of Selumetinib can be decreased when combined with Floxuridine.
Sulfaphenazole The metabolism of Selumetinib can be decreased when combined with Sulfaphenazole.
Secobarbital The metabolism of Selumetinib can be increased when combined with Secobarbital.
Trimethoprim The metabolism of Selumetinib can be decreased when combined with Trimethoprim.
Loratadine The metabolism of Selumetinib can be decreased when combined with Loratadine.
Quinine The metabolism of Selumetinib can be decreased when combined with Quinine.
Medroxyprogesterone acetate The metabolism of Selumetinib can be decreased when combined with Medroxyprogesterone acetate.
Irbesartan The metabolism of Selumetinib can be decreased when combined with Irbesartan.
Oxybutynin The metabolism of Selumetinib can be decreased when combined with Oxybutynin.
Fluvastatin The metabolism of Selumetinib can be decreased when combined with Fluvastatin.
Pioglitazone The metabolism of Selumetinib can be decreased when combined with Pioglitazone.
Genistein The metabolism of Selumetinib can be decreased when combined with Genistein.
Topiroxostat The metabolism of Selumetinib can be decreased when combined with Topiroxostat.
Eltrombopag The metabolism of Selumetinib can be decreased when combined with Eltrombopag.
Fluticasone propionate The metabolism of Selumetinib can be decreased when combined with Fluticasone propionate.
Clopidogrel The metabolism of Selumetinib can be decreased when combined with Clopidogrel.
Candesartan cilexetil The metabolism of Selumetinib can be decreased when combined with Candesartan cilexetil.
Salmeterol The metabolism of Selumetinib can be decreased when combined with Salmeterol.
Felodipine The metabolism of Selumetinib can be decreased when combined with Felodipine.
Fluticasone furoate The metabolism of Selumetinib can be decreased when combined with Fluticasone furoate.
Fluticasone The metabolism of Selumetinib can be decreased when combined with Fluticasone.
Mometasone furoate The metabolism of Selumetinib can be decreased when combined with Mometasone furoate.
Diethylstilbestrol The metabolism of Selumetinib can be decreased when combined with Diethylstilbestrol.
Osimertinib The serum concentration of Selumetinib can be decreased when it is combined with Osimertinib.
Vemurafenib The serum concentration of Selumetinib can be increased when it is combined with Vemurafenib.
Pitolisant The serum concentration of Selumetinib can be decreased when it is combined with Pitolisant.
Pravastatin Pravastatin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Pantoprazole Pantoprazole may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Gefitinib Gefitinib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Omeprazole The metabolism of Selumetinib can be decreased when combined with Omeprazole.
Beclomethasone dipropionate Beclomethasone dipropionate may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Progesterone Progesterone may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Dronabinol The metabolism of Selumetinib can be decreased when combined with Dronabinol.
Estradiol Estradiol may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Buprenorphine Buprenorphine may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Telmisartan Telmisartan may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Naringenin Naringenin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Quercetin Quercetin may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Taurocholic acid Taurocholic acid may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Elacridar Elacridar may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Vandetanib Vandetanib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Dovitinib Dovitinib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Safinamide Safinamide may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Vismodegib Vismodegib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Rilpivirine Rilpivirine may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Regorafenib Regorafenib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Afatinib Afatinib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Cannabidiol Cannabidiol may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Palbociclib Palbociclib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Daclatasvir Daclatasvir may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Dasabuvir Dasabuvir may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Rolapitant Rolapitant may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Paritaprevir Paritaprevir may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Alectinib Alectinib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Velpatasvir Velpatasvir may decrease the excretion rate of Selumetinib which could result in a higher serum level.

Target Protein

Dual specificity mitogen-activated protein kinase kinase 1 MAP2K1
Dual specificity mitogen-activated protein kinase kinase 2 MAP2K2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 29136201
    Seto T, Hirai F, Saka H, Kogure Y, Yoh K, Niho S, Fukase K, Shimada H, Sasai M, Fukino K: Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. Jpn J Clin Oncol. 2018 Jan 1;48(1):31-42. doi: 10.1093/jjco/hyx144.
  • PMID: 27751676
    Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15.
  • PMID: 28029918
    Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC: Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.
  • PMID: 22343622
    Holt SV, Logie A, Odedra R, Heier A, Heaton SP, Alferez D, Davies BR, Wilkinson RW, Smith PD: The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br J Cancer. 2012 Feb 28;106(5):858-66. doi: 10.1038/bjc.2012.8. Epub 2012 Feb 16.
  • PMID: 26871793
    Tchernev G, Chokoeva AA, Patterson JW, Bakardzhiev I, Wollina U, Tana C: Plexiform Neurofibroma: A Case Report. Medicine (Baltimore). 2016 Feb;95(6):e2663. doi: 10.1097/MD.0000000000002663.
  • PMID: 25385055
    Ciombor KK, Bekaii-Saab T: Selumetinib for the treatment of cancer. Expert Opin Investig Drugs. 2015 Jan;24(1):111-123. doi: 10.1517/13543784.2015.982275. Epub 2014 Nov 11.
  • PMID: 17126425
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7.
  • PMID: 20436278
    Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Basecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA: The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle. 2010 May;9(9):1781-91. doi: 10.4161/cc.9.9.11483. Epub 2010 May 10.
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Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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