Midostaurin

Midostaurin
Ball-and-stick model of the midostaurin molecule
Names
Trade namesRydapt, Tauritmo, others
Other namesPKC412, 4'-N-benzoylstaurosporine
IUPAC name
  • (9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesAcute myeloid leukemia (AML), systemic mastocytosis[2]
Side effectsFebrile neutropenia, peeling skin, vomiting, headache, bleeding into the skin[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    External links
    AHFS/Drugs.comMonograph
    Legal
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Chemical and physical data
    FormulaC35H30N4O4
    Molar mass570.649 g·mol−1
    3D model (JSmol)
    SMILES
    • C[C@@]12[C@@H]([C@@H](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC
    InChI
    • InChI=1S/C35H30N4O4/c1-35-32(42-3)25(37(2)34(41)19-11-5-4-6-12-19)17-26(43-35)38-23-15-9-7-13-20(23)28-29-22(18-36-33(29)40)27-21-14-8-10-16-24(21)39(35)31(27)30(28)38/h4-16,25-26,32H,17-18H2,1-3H3,(H,36,40)/t25-,26-,32-,35+/m1/s1
    • Key:BMGQWWVMWDBQGC-IIFHNQTCSA-N

    Midostaurin, sold under the brand name Rydapt among others, is a medication used to treat acute myeloid leukemia (AML) and systemic mastocytosis.[2] It is used in AML that has a FLT3 mutation.[1] It is taken by mouth.[2]

    Common side effects include febrile neutropenia, peeling skin, vomiting, headache, and bleeding into the skin.[1] Other side effects may include anaphylaxis, pneumonitis, infertility, and prolonged QT.[2] Use in pregnancy may harm the baby.[2] It is a tyrosine kinase inhibitor that blocks KIT kinase and FLT3 tyrosine kinase.[1]

    Midostaurin was approved for medical use in the United States and Europe in 2017.[2][1] In the United Kingdom 28 doses of 50 mg costs the NHS about £5,600 as of 2021.[3] This amount in the United States is about 9,900 USD.[4]

    Medical uses

    AML and MDS

    Midostaurin was found to be active against oncogenic CD135 (FMS-like tyrosine kinase 3 receptor, FLT3), in preclinical studies.[5] Clinical trials have primarily focused on relapsed/refractory AML and MDS and have included single agent and combination agent studies. After successful Phase II clinical trials, midostaurin was found to prolong survival of FLT3-mutated AML patients when combined with conventional induction and consolidation therapies in a randomized Phase III clinical trial.[6] On April 28, 2017, midostaurin was approved by the FDA for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.[7] The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

    Systemic mastocytosis

    Over 95% of people with adult onset systemic mastocytosis and approximately 40% of children with cutaneous mastocytosis are positive for the D816V c-Kit activating mutation, which renders c-Kit resistant to currently available tyrosine kinase inhibitors. Midostaurin is an investigational treatment in patients with advanced forms of systemic mastocytosis and D816V c-Kit mutation with a subset of patients achieving clinical response. In an open-label study of patients with mastocytosis-related organ damage (89 eligible patients meeting inclusion for the primary efficacy population), midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast cell leukemia.[8]

    Dosage

    For AML it is taken at a dose of 50 mg twice per day for two weeks every 4 weeks.[2] For mastocytosis it is used at a dose of 100 mg twice per day.[2]

    Side effects

    Common side effects include immune system related problems (fever, febrile neutropenia), blood clotting problems (bruising, nosebleed), and unspecific symptoms such as diarrhea, nausea and headache. Upper respiratory tract infections can be dangerous.[9]

    Chemistry

    It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

    History

    The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[10]

    References

    1. 1 2 3 4 5 6 "Rydapt". Archived from the original on 14 November 2021. Retrieved 18 November 2021.
    2. 1 2 3 4 5 6 7 8 "Midostaurin Monograph for Professionals". Drugs.com. Archived from the original on 12 July 2021. Retrieved 18 November 2021.
    3. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1034. ISBN 978-0857114105.
    4. ↑ "Rydapt Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 July 2021. Retrieved 18 November 2021.
    5. ↑ Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, et al. (June 2002). "Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412". Cancer Cell. 1 (5): 433–43. doi:10.1016/S1535-6108(02)00069-7. PMID 12124173.
    6. ↑ Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K, et al. (December 2015). The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). American Society of Hematology (ASH) 57th Annual Meeting. Orlando. Archived from the original on 2019-02-17. Retrieved 2021-08-24.
    7. ↑ Office of the Commissioner. "Press Announcements - FDA approves new combination treatment for acute myeloid leukemia". www.fda.gov. Archived from the original on 2017-05-02. Retrieved 2017-05-04.
    8. ↑ Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. (June 2016). "Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis". The New England Journal of Medicine. 374 (26): 2530–41. doi:10.1056/nejmoa1513098. PMID 27355533.
    9. ↑ Drugs.com: rydapt overview.
    10. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
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