Ivosidenib

Ivosidenib
Names
Pronunciationeye"voe sid' e nib
Trade namesTibsovo
Other namesAG-120
IUPAC name
  • (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
Clinical data
Drug classIsocitrate dehydrogenase-1 (IDH1) inhibitor[1]
Main usesAcute myeloid leukemia (AML), cholangiocarcinoma[2][3]
Side effectsDiarrhea, tiredness, swelling, nausea, abdominal pain, shortness of breath, QT prolongation, neuropathy, liver problems, low potassium, kidney problems[4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
MedlinePlusa618042
Legal
License data
Legal status
Chemical and physical data
FormulaC28H22ClF3N6O3
Molar mass582.97 g·mol−1
3D model (JSmol)
SMILES
  • 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 a medication used to treat acute myeloid leukemia (AML) and cholangiocarcinoma.[2][3] Specifically it is used in cases with IDH1 mutations.[4][3] It is taken by mouth.[4]

Common side effects include diarrhea, tiredness, swelling, nausea, abdominal pain, shortness of breath, QT prolongation, neuropathy, liver problems, low potassium, and kidney problems.[4] Other side effects may include Guillain–Barré syndrome and differentiation syndrome.[4] Use during pregnancy may harm the baby.[4] It is a isocitrate dehydrogenase-1 (IDH1) inhibitor that works by decreasing abnormal production of 2-hydroxyglutarate (2-HG), leading to differentiation of cancer cells.[1]

Ivosidenib was approved for medical use in the United States in 2018.[4] As of 2021 it is not approved in Europe or the United Kingdom.[5] In the United States it costs about 30,000 USD per month as of 2021.[6]

Medical uses

Ivosidenib is used for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.[1][7][8] It is also used for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in people who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.[9]

Additionally it may be used for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.[3]

Dosage

It is typically taken at a dose of 500 mg per day.[4]

Side effects

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

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[11] They also awarded it an orphan drug designation.[12][13][14][15]

Research

In tumors from patients 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.[16]

Ivosidenib, in in vitro studies, showed non-competitive inhibitory behavior towards the alpha-ketoglutarate (ɑ-KG) substrate and to the NADPH cofactor. This is what is believed to lead to Ivonsidenib being a rapid equilibrium inhibitor of the mIDH1-R132H homodimer, however NADPH is found to be pre-bound in recombinant enzyme preparations, which means this is not conclusive.

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.[17]

References

  1. 1 2 3 "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.
  2. 1 2 3 "Tibsovo- ivosidenib tablet, film coated". DailyMed. 24 April 2019. Archived from the original on 2 July 2019. Retrieved 18 December 2019.
  3. 1 2 3 4 "FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma". U.S. Food and Drug Administration (FDA). 26 August 2021. Archived from the original on 26 August 2021. Retrieved 26 August 2021.
  4. 1 2 3 4 5 6 7 8 "Ivosidenib Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2021. Retrieved 26 November 2021.
  5. ↑ "Ivosidenib". SPS - Specialist Pharmacy Service. 13 December 2017. Archived from the original on 11 December 2021. Retrieved 1 December 2021.
  6. ↑ "Tibsovo Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 26 February 2021. Retrieved 1 December 2021.
  7. ↑ "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.
  8. ↑ "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.
  9. ↑ "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.
  10. ↑ Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, et al. (2017-12-07). "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. Archived from the original on 2019-09-29. Retrieved 2021-08-27.
  11. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
  12. ↑ "Tibsovo Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 25 June 2021. Retrieved 18 December 2019.
  13. ↑ "Ivosidenib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 25 June 2021. Retrieved 18 December 2019.
  14. ↑ "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 10 July 2021. Retrieved 26 August 2021.
  15. ↑ "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 9 July 2021. Retrieved 26 August 2021.
  16. ↑ 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.
  17. ↑ 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.
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