Tibsovo (ivosidenib)

Ivosidenib, a potent and selective inhibitor of isocitrate dehydrogenase-1 (IDH1), is an antineoplastic agent.

Ivosidenib, a potent and selective inhibitor of isocitrate dehydrogenase-1 (IDH1), is an antineoplastic agent. Isocitrate dehydrogenases (IDH) are metabolic enzymes in the citric acid cycle responsible for the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, which is essential for normal cellular processes. Approximately 6-16% of acute myeloid leukemia (AML) cases carry IDH1 mutations.

IDH1 mutations cause a reduction of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate, which competitively inhibits alpha-ketoglutarate-dependent dioxygenases resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells.

Susceptible IDH1 mutations are defined as those resulting in increased 2-hydroxyglutarate levels in the leukemic cells and where efficacy of ivosidenib is predicted by clinically meaningful remissions at the recommended dosage of ivosidenib and/or inhibition of IDH1 mutation activity is expected at ivosidenib concentrations sustainable at the recommended dosage. The most common ivosidenib-susceptible IDH1 mutations are R132C and R132H substitution mutations. In vitro studies indicate that ivosidenib inhibits IDH1 with R132C, R132H, R132G, R132L, or R132S mutation at much lower concentrations than IDH1 wild-type enzymes.

Ivosidenib has demonstrated decreased 2-hydroxyglutarate levels and induction of myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH1 mutation and in mouse models of intra-hepatic cholangiocarcinoma. Ivosidenib also has demonstrated decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH1 mutation. The clinical importance of persistent IDH1 mutations in patients who achieve complete remission has not been established; however, persistent IDH1 mutations may indicate continued differentiation of abnormal myeloblast cells into mature granulocytes.

Peak plasma concentrations andAUC of ivosidenib are less than dose proportional over thedosage range of 200-1200 mg daily. Following oral administration of a single dose, median time to peak plasma concentrations of ivosidenib is approximately 2-3 hours. Following repeated administration of ivosidenib, steady-state concentrations of the drug are achieved in 14 days and accumulation of the drug is observed (approximately 1.2- to 1.9-fold increases in AUC and peak plasma concentrations).

Pharmacokinetics of ivosidenib at steady state in patients with newly diagnosed AML,patients with relapsed or refractory AML, and patients with relapsed or refractory MDSare similar, and are lower in patients with cholangiocarcinoma. Administration of ivosidenib (single 500-mg dose) with a high-fat meal (approximately 900-1000 calories with 500-600 calories from fat) increased peak plasma concentrations and AUC of ivosidenib by 98 and approximately 25%, respectively, in healthy individuals compared with administration in the fasted state; administration of ivosidenib with a high-fat meal should be avoided.

Ivosidenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by N-dealkylation and hydrolysis. Following oral administration of a radiolabeled dose of the drug, unchanged ivosidenib accounted for greater than 92% of plasma total radioactivity. In vitro, ivosidenib is highly bound (92-96%) to plasma proteins.

The terminal half-life at steady stateof ivosidenib is 129, 58,98,and 96hours in patients with cholangiocarcinoma, relapsed or refractory AML,newly diagnosed AML in combination with azacitidine, and relapsed or refractory MDS, respectively. Following administration of a radiolabeled dose of ivosidenib, 77% of the radioactivity was recovered in feces (67% of the dose as unchanged drug) and 17% was recovered in urine (10% of the dose as unchanged drug).

Clearance of ivosidenib does not appear to be affected substantially by age (18-89 years), sex, race, body weight (38-150 kg), or Eastern Cooperative Oncology Group (ECOG) performance status.

USES: This medication is used to treat certain types of blood cell cancer (acute myeloid leukemia-AML, myelodysplastic syndromes-MDS). Ivosidenib works by helping your bone marrow grow normal blood cells so you will need fewer blood transfusions. Ivosidenib is also used to treat bile duct cancer.

It works by slowing the growth of cancer cells.

Generic name: ivosidenib
Pronunciation: (EYE-voe-SID-e-nib)

The following indications are listed for Tibsovo:

• Acute Myeloid Leukemia With Isocitrate Dehydrogenase-1 (IDH1) Mutation
• Cholangiocarcinoma With Isocitrate Dehydrogenase-1 (IDH1) Mutation
• Myelodysplastic Syndrome With Isocitrate Dehydrogenase-1 (IDH1) Mutation

Also known as: Idh1 Mutated Cca, Idh1 Mutation-Positive Acute Myeloid Leukemia, Idh1 Mutation-Positive Cholangiocarcinoma.

No ICD codes are available for this drug.