Olutasidenib API Manufacturers

General Description:

Olutasidenib, identified by CAS number 1887014-12-1, is a notable compound with significant therapeutic applications. Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the FDA in December 2022. It is indicated for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH1 mutation as determined by an FDA-approved test. IDH1 mutations are common in different types of cancer, such as gliomas, AML, intrahepatic cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes (MDS), and they lead to an increase in 2-hydroxyglutarate (2-HG), a metabolite that participates in tumerogenesis. Olutasidenib inhibits the mutated IDH1 specifically, and provides a therapeutic benefit in IDH1-mutated cancers. Other IDH1 inhibitors, such as , have also been approved for the treatment of relapsed or refractory AML. Olutasidenib is orally bioavailable and capable of penetrating the blood-brain barrier, and is also being evaluated for the treatment of myelodysplastic syndrome (MDS), as well as solid tumors and gliomas (NCT03684811).

Indications:

This drug is primarily indicated for: Olutasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Olutasidenib undergoes metabolic processing primarily in: Olutasidenib is metabolized through N-dealkylation, demethylation, oxidative deamination followed by oxidation, and mono-oxidation with subsequent glucuronidation. Approximately 90% of the olutasidenib dose is metabolized by CYP3A4, while CYP2C8, CYP2C9, CYP1A2, and CYP2C19 play a minor role. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Olutasidenib are crucial for its therapeutic efficacy: In patients with acute myeloid leukemia (AML) given the recommended dosage, the steady-state daily area under the plasma drug concentration over time curve (AUC0-12-h, ss) of olutasidenib is 43050 ng⋅h/mL, and its steady-state C_max is 3573 ng/mL. The C_max and AUC of olutasidenib increase in a less-than proportionally manner between 100 mg and 300 mg (0.33 to 1 time the recommended total daily dose); however, no changes in the recommended dosage are required. In patients given a single oral dose of 150 mg, the median t_max of olutasidenib is approximately 4 hours. In healthy subjects, the administration of a single dose (150 mg) of olutasidenib with a high-fat meal (800-1,000 calories, 50% of total caloric content of the meal from fat) leads to a 191% and 83% increase of the C_max and AUC_inf, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Olutasidenib is an important consideration for its dosing schedule: Olutasidenib has a mean half-life of 67 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Olutasidenib exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of olutasidenib is approximately 93%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Olutasidenib from the body primarily occurs through: In healthy subjects given a single dose (150 mg) of radiolabeled olutasidenib orally, approximately 17% of olutasidenib was recovered in urine (1% unchanged), while 75% was recovered in feces (35% unchanged). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Olutasidenib is distributed throughout the body with a volume of distribution of: Olutasidenib has an apparent volume of distribution of 319 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Olutasidenib is a critical factor in determining its safe and effective dosage: Olutasidenib has a mean apparent oral clearance (CL/F) of 4 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Olutasidenib exerts its therapeutic effects through: In patients with acute myeloid leukemia (AML) and IDH1 mutations, olutasidenib led to a 59.1% reduction in 2-hydroxyglutarate (2-HG) levels by pre-dose Cycle 2. The reduction in 2-HG levels was maintained throughout the treatment period. A correlation between increased olutasidenib exposure and an increased probability of differentiation syndrome and grade 3 hepatotoxicity was also detected in AML patients treated with olutasidenib. The use of olutasidenib leads to a concentration-dependent increase in QTc interval; however, the impact of this increase could not be defined since higher exposures of olutasidenib were not evaluated. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Olutasidenib functions by: Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor used to treat patients with acute myeloid leukemia (AML) and IDH1 genetic mutations associated with cancer development. IDH1 catalyzes the oxidative decarboxylation of isocitrate to form α-ketoglutarate (α-KG). However, mutations in IDH1 occur in the active catalytic sites of the arginine residues and promote the conversion of α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to the formation of tumors. This causes an increase in 2-HG levels, inhibiting α-KG-dependent mechanisms, such as epigenetic regulation, collagen synthesis and cell signaling. IDH1 mutations have been detected in different types of cancers, including AML, and some of the most common IDH1 mutations in patients with AML are R132H and R132C substitutions. Olutasidenib acts as a selective IDH1 inhibitor with affinity only towards the mutated enzyme. _In vitro_ studies have shown that olutasidenib inhibits mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins, but not wild-type IDH1 or mutated IDH2 proteins. Through the inhibition of mutant IDH1, olutasidenib reduces 2-HG levels, which promotes the restoration of normal cellular differentiation and provides a therapeutic benefit in IDH1-mutated cancers. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Olutasidenib is categorized under the following therapeutic classes: Antineoplastic Agents, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Substrates, Enzyme Inhibitors, Heterocyclic Compounds, Fused-Ring, Isocitrate dehydrogenase-1 (IDH1) inhibitors, Isocitrate Dehydrogenase-1 Inhibitors, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, OAT3/SLC22A8 Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, OCT2 Inhibitors, P-glycoprotein inhibitors, Potential QTc-Prolonging Agents, QTc Prolonging Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Olutasidenib include:

• Water Solubility: Insoluble