What Is Ivosidenib (Tibsovo)? FDA Approval History

• FDA approved: Yes (first approval date: 20 July 2018)
• Active ingredient: Ivosidenib
• Brand name: Tibsovo
• Route of administration: Tablet (available as 250 mg tablets)
• Class: Signal transduction inhibitor, IDH1 inhibitor
• Category: Targeted agent
• Manufacturer: Servier Pharmaceuticals
• Distribution in Turkey: Not yet available
• Approved cancers: Acute myeloid leukemia (AML), cholangiocarcinoma, and myelodysplastic syndromes (MSD). Patients should be selected based on the presence of IDH1 mutations in blood, bone marrow, or tumor tissue.

Mechanism of Action of Ivosidenib

Ivosidenib inhibits the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, suppressing its activity. IDH1 normally converts isocitrate, a type of energy molecule, into alpha-ketoglutarate. Mutant IDH1, however, converts alpha-ketoglutarate into an abnormal metabolite, 2-hydroxyglutarate (2-HG). Accumulation of 2-HG blocks cellular differentiation and promotes the formation and growth of malignant (cancerous) cells.

By inhibiting mutant IDH1 enzyme activity, ivosidenib reduces 2-HG levels. This reduction in 2-HG triggers myeloid differentiation and increases the number of mature myeloid cells.

This mechanism explains how ivosidenib can be used to treat diseases with IDH1 mutations, such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and cholangiocarcinoma. By reducing abnormal 2-HG production, ivosidenib allows malignant cells to differentiate, helping control and treat the disease.

FDA Approval Timeline for Ivosidenib

• 20 July 2018: Tibsovo (ivosidenib) was approved for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
• 2 May 2019: Tibsovo was approved as monotherapy for adults with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
• 25 August 2021: Tibsovo was approved for IDH1-mutated cholangiocarcinoma (bile duct cancer).
• 25 May 2022: Tibsovo was approved in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia.
• 24 October 2023: Tibsovo was approved to treat IDH1-mutated relapsed or refractory myelodysplastic syndromes (MDS).

Licensing and Reimbursement Status of Ivosidenib in Turkey

Tibsovo, which contains ivosidenib, has not yet been licensed by Turkey's Ministry of Health. It has also not yet been included in reimbursement coverage by SGK (the Social Security Institution).

Because the drug is not available in Turkey, the treating medical oncologist must first obtain off-label approval from the Ministry of Health if its use is intended. Following approval, it can be imported on prescription through the Turkish Pharmacists' Association (TEB), provided the patient pays the cost. In some cases, after the Ministry's off-label approval, the drug can also be obtained through TEB by court order.

Mechanism of Resistance

No well-characterized mechanism has been identified to date.

Absorption

Oral bioavailability is 77%. Peak drug levels occur 1.3-1.8 hours after administration. High-fat food reduces AUC by 16% and Cmax by 31%. AUC indicates how long the drug spends in the body and how much is absorbed. Cmax indicates the highest level the drug reaches in the body. This information suggests that high-fat meals may reduce the drug's effectiveness.

Distribution

Plasma proteins bind 91% of drug molecules. Steady-state levels are reached in about 8 days.

Metabolism

Most of the drug is metabolized in the liver, primarily by CYP3A4 microsomal enzymes, with minor contributions from CYP2C8 and UGT1A9. Of an administered dose, 49% is excreted in urine and 42% in feces. The terminal half-life is approximately 17.4 hours.

Dose Range

The recommended dose is 500 mg orally once daily, equivalent to 2 tablets of 250 mg. Tablets may be taken with or without food. Taking them at the same time each day is recommended.

For 1 box (60 oral tablets of 250 mg), the United States price is 31687 dollars.

Drug Interactions

• Drugs such as ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole may slow ivosidenib metabolism, increasing drug levels and potentially toxicity.
• Drugs such as rifampin, phenytoin, phenobarbital, carbamazepine, and St. John's Wort may speed ivosidenib metabolism, leading to lower effective drug levels.

Special Precautions

• Hepatic Impairment: No dose adjustment is required for mild or moderate hepatic impairment. The drug has not been studied in severe hepatic impairment, and no official dose recommendations are available in this setting.
• Renal Impairment: No dose adjustment is required for mild or moderate renal impairment (CrCl >30 mL/min). The drug has not been studied in severe renal impairment or in patients on hemodialysis, and no official dose recommendations are available in these settings.
• Monitoring and Tests:
  • Monitor a complete blood count and blood chemistry at baseline, at least weekly during the first month, every two weeks during the second month, and monthly throughout treatment.
  • Monitor serum CPK levels weekly during the first month of treatment.
  • Because ivosidenib can prolong the QTc interval on ECG, monitor ECG at least weekly during the first 3 weeks and at least monthly thereafter throughout treatment. Avoid concomitant use of other drugs that may prolong the QTc interval.
  • If a strong CYP3A4 inhibitor must be given concomitantly, reduce the ivosidenib dose.
• Differentiation Syndrome: Differentiation syndrome is a complication of ivosidenib therapy and can be life-threatening if not properly treated. It can occur as early as 10 days and as late as 5 months after treatment begins. If it develops, start dexamethasone 10 mg IV every 12 hours and monitor patients hemodynamically until improvement. If leukocytosis occurs without infection, start hydroxyurea or leukapheresis. This is a black box warning.
• Neuropathy and Guillain-Barre Syndrome: Because ivosidenib has been associated with Guillain-Barre syndrome, monitor patients for signs or symptoms of motor and/or sensory neuropathy.
• Pregnancy and Contraception: Administration during pregnancy may cause fetal harm. Women of reproductive potential should use effective contraception during treatment and for at least 30 days after the last dose. Breastfeeding should be avoided.

Adverse Effects

Common adverse effects in patients receiving ivosidenib for cholangiocarcinoma include fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and loss of appetite. These adverse effects were observed in the trial that led to FDA approval of ivosidenib for cholangiocarcinoma, Study AG120-C-005, and occurred in more than 20% of the participating patients.

The drug's general adverse effects are as follows, from more to less common:

1. Myelosuppression (reduced blood counts), with anemia, thrombocytopenia, and neutropenia.
2. Diarrhea, nausea/vomiting, and abdominal pain.
3. IDH differentiation syndrome, with dyspnea, hypoxia, pulmonary infiltrates, pleural effusion, fever, bone pain, peripheral edema, and pericardial effusion. Hepatic, renal, and multiorgan dysfunction have also been observed.
4. Fatigue and anorexia (reduced appetite, weight loss).
5. QTc prolongation on ECG.
6. Guillain-Barre syndrome.