Peringatan Keamanan

In a fertility study involving female and male rats, there is evidence of reproductive toxicity including reduced sperm count and decline pregnancy rates when administering 0.01 to 0.1 times the recommended dose in humans. Incidences of pulmonary toxicities including interstitial lung disease and pneumonitis have occured in few patients undergoing midostaurin monotherapy or combination therapy.

Midostaurin

DB06595

small molecule approved investigational

Deskripsi

Midostaurin (as Rydapt) is a multitarget kinase inhibitor for the treatment for adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3. It was initially characterized as a potential broad-spectrum antineoplastic agent, with activity toward diverse solid and hematopoietic tumors A19108. It was approved on April 28, 2017 and has shown to increase the overall survival rate in patients with AML as an adjunct therapy along with chemotherapeutic agents.

Struktur Molekul 2D

Berat 570.649
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Elimination half life is approximately 21 hrs for midostaurin, 32 hrs for CGP62221 and 482 hrs for CGP52421.
Volume Distribusi The Vd of midostaurin is 95.2L. The parent drug and its main metabolites (CGP62221, CGP52421) are distributed in plasma in vitro.
Klirens (Clearance) The clearance values of during the initial formation of metabolites are 1.47 L/h for CGP62221 metabolite and 0.501 L/h for CGP52421. 28 days following the oral administration of midostaurin, the clearance of CGP52421 may increase up to 5.2 fold in a recommended dose of 25 mg, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin [A19109].

Absorpsi

The time to reach maximum concentration ranges from 1-3 hrs in fasting patients. The maximum concentration and the time it takes to reach this concentration is reduced up to 20% in presence of a standard meal.

Metabolisme

Midostaurin is primarily metabolized into CGP62221 and CGP52421 via hepatic CYP3A4 enzymatic activity. The metabolism of CGP62221 takes place initially in a linear relationship whereas CGP52421 formation is an inducible process A19109.

Rute Eliminasi

Accounting for 95% of recovered dose eliminated through fecal excretion, 91% was determined as metabolites and 4% as unchanged parent drug. Remaining 5% of the recovered dose is eliminated via renal excretion.

Interaksi Makanan

3 Data
  • 1. Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of midostaurin and may reduce its serum concentration.
  • 2. Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of midostaurin, which may increase its serum concentration.
  • 3. Take with food. Taking midostaurin with food increases the AUC, but it also prolongs the Tmax and reduces Cmax.

Interaksi Obat

1010 Data
Armodafinil The metabolism of Midostaurin can be increased when combined with Armodafinil.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Midostaurin.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Midostaurin.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Midostaurin.
Colchicine The metabolism of Colchicine can be decreased when combined with Midostaurin.
Fentanyl The metabolism of Fentanyl can be decreased when combined with Midostaurin.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Midostaurin.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Midostaurin.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Midostaurin.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Midostaurin.
Metreleptin The metabolism of Midostaurin can be increased when combined with Metreleptin.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Midostaurin.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Midostaurin.
Perampanel The metabolism of Perampanel can be increased when combined with Midostaurin.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Midostaurin.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Midostaurin.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Midostaurin.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Midostaurin.
Crizotinib The metabolism of Midostaurin can be decreased when combined with Crizotinib.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Midostaurin.
Erlotinib The metabolism of Erlotinib can be decreased when combined with Midostaurin.
Segesterone acetate The metabolism of Segesterone acetate can be increased when combined with Midostaurin.
Nafcillin The metabolism of Midostaurin can be increased when combined with Nafcillin.
Avasimibe The metabolism of Midostaurin can be increased when combined with Avasimibe.
Echinacea The metabolism of Midostaurin can be increased when combined with Echinacea.
Lesinurad The metabolism of Midostaurin can be increased when combined with Lesinurad.
Rufinamide The metabolism of Midostaurin can be increased when combined with Rufinamide.
Genistein The metabolism of Midostaurin can be increased when combined with Genistein.
Topiramate The metabolism of Midostaurin can be increased when combined with Topiramate.
Oritavancin The metabolism of Midostaurin can be increased when combined with Oritavancin.
Glycerol phenylbutyrate The metabolism of Midostaurin can be increased when combined with Glycerol phenylbutyrate.
Eslicarbazepine acetate The metabolism of Midostaurin can be increased when combined with Eslicarbazepine acetate.
Sarilumab The metabolism of Midostaurin can be increased when combined with Sarilumab.
Methylphenobarbital The metabolism of Midostaurin can be increased when combined with Methylphenobarbital.
Barbital The metabolism of Midostaurin can be increased when combined with Barbital.
Troglitazone The metabolism of Midostaurin can be increased when combined with Troglitazone.
Fluticasone The metabolism of Midostaurin can be increased when combined with Fluticasone.
Phenylbutazone The metabolism of Midostaurin can be increased when combined with Phenylbutazone.
Butalbital The metabolism of Midostaurin can be increased when combined with Butalbital.
Flucloxacillin The metabolism of Midostaurin can be increased when combined with Flucloxacillin.
Aminoglutethimide The metabolism of Midostaurin can be increased when combined with Aminoglutethimide.
Griseofulvin The metabolism of Midostaurin can be increased when combined with Griseofulvin.
Secobarbital The metabolism of Midostaurin can be increased when combined with Secobarbital.
Dicloxacillin The metabolism of Midostaurin can be increased when combined with Dicloxacillin.
Hydrocortamate The metabolism of Midostaurin can be increased when combined with Hydrocortamate.
Oxcarbazepine The metabolism of Midostaurin can be increased when combined with Oxcarbazepine.
Metyrapone The metabolism of Midostaurin can be increased when combined with Metyrapone.
Probenecid The metabolism of Midostaurin can be increased when combined with Probenecid.
Cefradine The metabolism of Midostaurin can be increased when combined with Cefradine.
Amobarbital The metabolism of Midostaurin can be increased when combined with Amobarbital.
Aprobarbital The metabolism of Midostaurin can be increased when combined with Aprobarbital.
Deferasirox The metabolism of Midostaurin can be increased when combined with Deferasirox.
Formestane The metabolism of Midostaurin can be increased when combined with Formestane.
Barbexaclone The metabolism of Midostaurin can be increased when combined with Barbexaclone.
Eslicarbazepine The metabolism of Midostaurin can be increased when combined with Eslicarbazepine.
Prednisolone hemisuccinate The metabolism of Midostaurin can be increased when combined with Prednisolone hemisuccinate.
Prednisone acetate The metabolism of Midostaurin can be increased when combined with Prednisone acetate.
Clocortolone acetate The metabolism of Midostaurin can be increased when combined with Clocortolone acetate.
Melengestrol acetate The metabolism of Midostaurin can be increased when combined with Melengestrol acetate.
Mometasone The metabolism of Midostaurin can be increased when combined with Mometasone.
Fluconazole The metabolism of Midostaurin can be decreased when combined with Fluconazole.
Ciprofloxacin The metabolism of Midostaurin can be decreased when combined with Ciprofloxacin.
Isoniazid The metabolism of Midostaurin can be decreased when combined with Isoniazid.
Miconazole The metabolism of Midostaurin can be decreased when combined with Miconazole.
Zimelidine The metabolism of Midostaurin can be decreased when combined with Zimelidine.
Seproxetine The metabolism of Midostaurin can be decreased when combined with Seproxetine.
Propofol The metabolism of Midostaurin can be decreased when combined with Propofol.
Cimetidine The metabolism of Midostaurin can be decreased when combined with Cimetidine.
Quinupristin The metabolism of Midostaurin can be decreased when combined with Quinupristin.
Dalfopristin The metabolism of Midostaurin can be decreased when combined with Dalfopristin.
Vapreotide The metabolism of Midostaurin can be decreased when combined with Vapreotide.
Dovitinib The metabolism of Midostaurin can be decreased when combined with Dovitinib.
Pasireotide The metabolism of Midostaurin can be decreased when combined with Pasireotide.
Lanreotide The metabolism of Midostaurin can be decreased when combined with Lanreotide.
Somatostatin The metabolism of Midostaurin can be decreased when combined with Somatostatin.
Glecaprevir The metabolism of Midostaurin can be decreased when combined with Glecaprevir.
Bifonazole The metabolism of Midostaurin can be decreased when combined with Bifonazole.
Fluoxetine The metabolism of Midostaurin can be decreased when combined with Fluoxetine.
Ginkgo biloba The metabolism of Midostaurin can be decreased when combined with Ginkgo biloba.
Ethambutol The metabolism of Midostaurin can be decreased when combined with Ethambutol.
Zafirlukast The serum concentration of Midostaurin can be increased when it is combined with Zafirlukast.
Irbesartan The serum concentration of Midostaurin can be increased when it is combined with Irbesartan.
Sulfamethoxazole The serum concentration of Midostaurin can be increased when it is combined with Sulfamethoxazole.
Sitaxentan The serum concentration of Midostaurin can be increased when it is combined with Sitaxentan.
Indisulam The serum concentration of Midostaurin can be increased when it is combined with Indisulam.
Mequitazine The serum concentration of Midostaurin can be increased when it is combined with Mequitazine.
Letermovir The serum concentration of Midostaurin can be increased when it is combined with Letermovir.
Capsaicin The risk or severity of methemoglobinemia can be increased when Midostaurin is combined with Capsaicin.
Metronidazole The serum concentration of Midostaurin can be increased when it is combined with Metronidazole.
Desipramine The serum concentration of Midostaurin can be increased when it is combined with Desipramine.
Aldesleukin The serum concentration of Midostaurin can be increased when it is combined with Aldesleukin.
Chloramphenicol The serum concentration of Midostaurin can be increased when it is combined with Chloramphenicol.
Raloxifene The serum concentration of Midostaurin can be increased when it is combined with Raloxifene.
Niacin The serum concentration of Midostaurin can be increased when it is combined with Niacin.
Epinephrine The serum concentration of Midostaurin can be increased when it is combined with Epinephrine.
Acetazolamide The serum concentration of Midostaurin can be increased when it is combined with Acetazolamide.
Clofazimine The serum concentration of Midostaurin can be increased when it is combined with Clofazimine.
Dirithromycin The serum concentration of Midostaurin can be increased when it is combined with Dirithromycin.
Dimethyl sulfoxide The serum concentration of Midostaurin can be increased when it is combined with Dimethyl sulfoxide.
Candicidin The serum concentration of Midostaurin can be increased when it is combined with Candicidin.

Target Protein

Protein kinase C gamma type PRKCG
Protein kinase C alpha type PRKCA
Vascular endothelial growth factor receptor 2 KDR
Platelet-derived growth factor receptor alpha PDGFRA
Platelet-derived growth factor receptor beta PDGFRB
Receptor-type tyrosine-protein kinase FLT3 FLT3
Mast/stem cell growth factor receptor Kit KIT

Referensi & Sumber

Artikel (PubMed)
  • PMID: 20733134
    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ: Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. doi: 10.1200/JCO.2010.28.9678. Epub 2010 Aug 23.
  • PMID: 16969355
    Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12.
  • PMID: 27355533
    Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A: Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
  • PMID: 27186148
    Gallogly MM, Lazarus HM: Midostaurin: an emerging treatment for acute myeloid leukemia patients. J Blood Med. 2016 Apr 19;7:73-83. doi: 10.2147/JBM.S100283. eCollection 2016.
  • PMID: 19026036
    Yin OQ, Wang Y, Schran H: A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects. Clin Pharmacokinet. 2008;47(12):807-16. doi: 10.2165/0003088-200847120-00005.

Contoh Produk & Brand

Produk: 4 • International brands: 0
Produk
  • Rydapt
    Capsule • 25 mg • Oral • EU • Approved
  • Rydapt
    Capsule • 25 mg • Oral • EU • Approved
  • Rydapt
    Capsule • 25 mg • Oral • Canada • Approved
  • Rydapt
    Capsule, liquid filled • 25 mg/1 • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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