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IDH 1 Inhibitor

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IDH 1 Inhibitor, Isocitrate Dehydrogenase 1 Inhibitor, Ivosidenib, Tibsovo

  • See Also
  1. IDH 2 Inhibitor
  2. Small Molecule Inhibitor-Mediated Chemotherapy
  3. Chemotherapy
  • Indications
  1. Acute Myelogenous Leukemia (IDH1/2+ new or advanced/refractory)
  • Mechanism
  1. Isocitrate Dehydrogenase (IDH)
    1. Isocitrate Dehydrogenase is a cytoplasmic enzyme that decarboxylating isocitrate to alpha ketoglutarate
    2. Rate limiting step of the TCA Cycle (Kreb Cycle)
    3. Isocitrate Dehydrogenase (IDH) has 3 forms with the same activity (the first 2 are associated with cancers)
      1. IDH1 is found in cytoplasm (and encoded by gene 2q33)
      2. IDH2 is found in mitochondria (and encoded by gene 15q26)
  2. IDH1 Mutations
    1. Associated with Acute Myelogenous Leukemia (similar to IDH2)
    2. In contrast to IDH2, IDH1 is also associated with other cancers (e.g. glioblastoma, low grade gliomas)
    3. Triggers abnormal levels of 2-Hydroxyglutarate (2-HG)
    4. 2-HG inhibits histone and DNA demethylases
      1. Alters gene expression, and may promote cancer growth
  • Medications
  1. Ivosidenib (Tibsovo)
    1. Risk of Differentiation Syndrome, Prolonged QTc, Guillain Barre Syndrome
    2. Avoid with high fat meals (increased risk of toxicity)
  • Dosing
  1. See other references for disease specific dosing protocols
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
  3. Monitoring
    1. Electrocardiogram (for QTc Prolongation)
  • Adverse Effects
  1. Differentiation Syndrome (Ivosidenib)
    1. Life threatening condition, rapid myeloid cell proliferation and differentiation
    2. May present with acute respiratory distress, Acute Kidney Injury, fever, edema
    3. Onset in the first 10 weeks of therapy requiring prompt initiation of Corticosteroids
  2. Prolonged QTc (Ivosidenib)
    1. Avoid in known QTc Prolongation or Serum Electrolyte abnormalities (Hypomagnesemia, Hypokalemia)
    2. Avoid with other Medication Causes of QTc Prolongation
  3. Guillain Barre Syndrome (Ivosidenib)
  4. Other reported adverse effects
    1. Edema
    2. Hepatotoxicity
  • Drug Interactions
  1. Strong CYP3A4 Inhibitors
    1. Decrease Ivosidenib dose
  2. Strong CYP3A4 Inducers
    1. Avoid with Ivosidenib
  3. CYP3A4 substrates with narrow Therapeutic Index
    1. Avoid with Ivosidenib
  4. Medication Causes of QTc Prolongation
    1. Avoid with Ivosidenib
  • Resources
  1. Ivosidenib (Tibsovo)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5b6d8ae8-bac8-4e1b-b1b4-7f9665e62de5
  • References
  1. Liu (2020) Curr Opin Chem Biol 57:122-34 +PMID: 32777735 [PubMed]