Introduction
Tibsovo (ivosidenib) is an oral, targeted anticancer agent developed by Servier Pharmaceuticals. It is a first-in-class isocitrate dehydrogenase-1 (IDH1) inhibitor approved for the treatment of specific hematologic malignancies with IDH1 mutations. Tibsovo represents a significant advancement in precision medicine for patients with acute myeloid leukemia (AML) and cholangiocarcinoma.
Mechanism of Action
Tibsovo works as a small molecule inhibitor of the mutated isocitrate dehydrogenase 1 (IDH1) enzyme. In patients with IDH1 mutations, the enzyme produces abnormally high levels of the oncometabolite 2-hydroxyglutarate (2-HG), which blocks normal cellular differentiation and promotes leukemogenesis. Ivosidenib selectively targets and inhibits the mutant IDH1 enzyme, reducing 2-HG levels and allowing for differentiation of malignant blasts into mature, functional myeloid cells.
Indications
- Newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in adults ≥75 years or who have comorbidities that preclude use of intensive induction chemotherapy
- Relapsed or refractory AML with a confirmed IDH1 mutation in adults
- Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation in adults
Dosage and Administration
Standard dosing: 500 mg orally once daily with or without food Treatment duration: Continue until disease progression or unacceptable toxicity Dose modifications:- For adverse reactions: Interrupt therapy, then resume at 250 mg once daily or 500 mg once daily based on severity
- For concomitant use with strong CYP3A4 inhibitors: Reduce dose to 250 mg once daily
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment; use with caution in severe impairment
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment; use with caution in severe impairment
Pharmacokinetics
Absorption: Median Tmax is 3 hours (range 1.5-4.5 hours); high-fat meal decreases Cmax by 27% and AUC by 19% Distribution: Apparent volume of distribution is 213 L; protein binding is 93% Metabolism: Primarily metabolized by CYP3A4 with minor contributions from CYP2C8 and UGT1A1 Elimination: Half-life is 93 hours; fecal excretion (77%) predominates over renal excretion (17%)Contraindications
- History of serious hypersensitivity reactions to ivosidenib or any component of the formulation
- Concomitant use with strong CYP3A4 inducers (may decrease ivosidenib concentrations)
Warnings and Precautions
Differentiation Syndrome: Occurs in ~25% of patients; can be fatal if not treated. Monitor for fever, dyspnea, hypoxia, pulmonary infiltrates, pleural/pericardial effusions, rapid weight gain, peripheral edema, or hepatic/renal dysfunction. Treat promptly with corticosteroids and hemodynamic support. QTc Prolongation: Can occur; monitor ECGs and electrolytes periodically. Avoid concomitant use with drugs known to prolong QTc interval. Guillain-Barré Syndrome: Has been reported; monitor for motor and/or sensory neuropathy symptoms. Hepatotoxicity: Liver enzyme elevations occur; monitor liver function tests regularly.Drug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase ivosidenib exposure; reduce Tibsovo dose to 250 mg once daily Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease ivosidenib exposure; contraindicated Moderate CYP3A4 inducers (e.g., bosentan, efavirenz): May decrease ivosidenib exposure; avoid concomitant use QTc-prolonging drugs (e.g., antiarrhythmics, certain antipsychotics): Increased risk of QTc prolongation; avoid or monitor closelyAdverse Effects
Most common (≥20%): Fatigue, arthralgia, diarrhea, dyspnea, edema, nausea, decreased appetite, leukocytosis, rash, fever, constipation, mucositis Serious adverse reactions: Differentiation syndrome (25%), leukocytosis (39%), QTc prolongation (26%), Guillain-Barré syndrome (rare) Laboratory abnormalities: Decreased potassium, calcium, phosphate; increased alkaline phosphatase, bilirubin, ALT/ASTMonitoring Parameters
- IDH1 mutation status prior to initiation
- Complete blood count with differential weekly for first month, then at least monthly
- Liver function tests at least weekly for first month, then monthly
- ECG and electrolytes at baseline, weekly during first 3 weeks, then periodically
- Signs/symptoms of differentiation syndrome daily during first 3 weeks
- Neurological symptoms for Guillain-Barré syndrome
- Pregnancy status in women of reproductive potential
Patient Education
- Take Tibsovo exactly as prescribed at the same time each day
- Swallow tablets whole; do not break, crush, or chew
- May be taken with or without food
- Report any signs of infection, fever, difficulty breathing, rapid weight gain, or swelling immediately
- Inform all healthcare providers about Tibsovo use, especially before starting new medications
- Use effective contraception during treatment and for at least 1 month after final dose
- Do not breastfeed during treatment and for at least 1 month after final dose
- Regular blood tests and heart monitoring are necessary during treatment
References
1. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. 2. Tibsovo [package insert]. Cambridge, MA: Servier Pharmaceuticals LLC; 2023. 3. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 4.2023. 4. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807. 5. FDA Approval: Tibsovo (ivosidenib) for AML. FDA.gov. Accessed January 2023. 6. Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces hematologic responses in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2020;34(4):1157-1160.