Ivosidenib

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Ivosidenib
Ivosidenib.svg
Clinical data
Pronunciationeye"voe sid' e nib
Trade namesTibsovo
Other namesAG-120
AHFS/Drugs.comMonograph
MedlinePlusa618042
License data
Routes of
administration
By mouth
Drug classAntineoplastic Agents
ATC code
Legal status
Legal status
Identifiers
  • (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3- difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC28H22ClF3N6O3
Molar mass582.97 g·mol−1
3D model (JSmol)
  • C1CC(=O)N(C1C(=O)N(C2=CC(=CN=C2)F)C(C3=CC=CC=C3Cl)C(=O)NC4CC(C4)(F)F)C5=NC=CC(=C5)C#N

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma.[1] It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.[3]

Ivosidenib was approved for medical use in the United States in July 2018.[3][4][5][6] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[7]

Medical uses[edit]

Ivosidenib is indicated for people with acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma.[1][8][9]

Adverse effects[edit]

In ivosidenib-treated patients, reported adverse effects have been febrile neutropenia, alanine aminotransferase increased, aspartate aminotransferase increased, colitis, hypertension, maculopapular rash. However, Ivosidenib was taken in conjunction with standard AML induction treatment, and side effects can not be directly related to the drug.[10]

History[edit]

The US Food and Drug Administration (FDA) awarded orphan drug designations for acute myeloid leukemia and for cholangiocarcinoma.[11][12][13][14]

Research[edit]

In tumors from people diagnosed with glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma, somatic mutations in the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 are observed. With these new mutations, these enzymes exhibit new, neomorphic behavior, which results in the reduction of α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate. The new molecule competitively inhibits α-ketoglutarate–dependent enzymes, ultimately leading to epigenetic alterations and impaired hematopoietic differentiation. Mutations in the IDH1 enzyme mutations occur in approximately 6 to 10% of the patients with AML, and IDH2 mutations occur in approximately 9 to 13% of those with AML, with unknown statistics on other conditions listed.[15]

The drug is also believed to believed to be a slow-binding inhibitor of the IDH1-WT homodimer. Ivosidenib showed uncompetitive inhibition to the NADP cofactor, showing a hyperbolic curve for the rate constant of inhibition relative to concentration. Ivosidenib also showed no time-dependence in IC50 between 1 and 16 hours of incubation for either homodimer.[16]

References[edit]

  1. ^ a b c "Tibsovo- ivosidenib tablet, film coated". DailyMed. 24 April 2019. Retrieved 18 December 2019.
  2. ^ "Tibsovo- ivosidenib tablet, film coated". DailyMed. 9 June 2022. Retrieved 3 December 2022.
  3. ^ a b "FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation". U.S. Food and Drug Administration (FDA) (Press release). 20 July 2018. Archived from the original on 11 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  4. ^ "Drug Trials Snapshots: Tibsovo". U.S. Food and Drug Administration (FDA). 2 August 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ "FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia". U.S. Food and Drug Administration (FDA). 23 January 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ^ "Drug Approval Package: Tibsovo (ivosidenib)". U.S. Food and Drug Administration (FDA).
  7. ^ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  8. ^ "FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation". U.S. Food and Drug Administration (FDA). 3 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  9. ^ "FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma". U.S. Food and Drug Administration (FDA). 26 August 2021. Retrieved 26 August 2021.
  10. ^ Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, et al. (7 December 2017). "Ivosidenib or Enasidenib Combined with Standard Induction Chemotherapy Is Well Tolerated and Active in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation: Initial Results from a Phase 1 Trial". Blood. 130 (Suppl 1): 726. doi:10.1182/blood.V130.Suppl_1.726.726.
  11. ^ "Tibsovo Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 18 December 2019.
  12. ^ "Ivosidenib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 18 December 2019.
  13. ^ "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 26 August 2021.
  14. ^ "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 26 August 2021.
  15. ^ DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. (June 2018). "Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML". The New England Journal of Medicine. 378 (25): 2386–2398. doi:10.1056/NEJMoa1716984. PMID 29860938. S2CID 205102890.
  16. ^ Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers". ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.

External links[edit]

  • "Ivosidenib". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02074839 for "Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation" at ClinicalTrials.gov
  • Clinical trial number NCT02989857 for "Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) (ClarIDHy)" at ClinicalTrials.gov