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General Description:

Ivosidenib, identified by CAS number 1448347-49-6, is a notable compound with significant therapeutic applications. Ivosidenib is a first-in-class isocitrate dehydrogenase-1 (IDH1) inhibitor. IDH1 is an enzyme that is often mutated and overexpressed in some cancers, leading to aberrant cell growth and proliferation. Ivosidenib inhibits mutated IDH1, blocking the enzymatic activity and further differentiation of cancer cells. Ivosidenib was granted accelerated approval by the FDA in July 2018 for the treatment of relapsed of refractory acute myeloid leukemia in adults. It is currently approved to also treat newly diagnosed acute myeloid leukemia in older adults in combination or as monotherapy, as well as locally advanced or metastatic cholangiocarcinoma in adults. The drug is only effective in patients with a susceptible IDH1 mutation.

Indications:

This drug is primarily indicated for: Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: - Newly Diagnosed Acute Myeloid Leukemia (AML) in combination or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. - Relapsed or refractory AML in adults. - Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ivosidenib undergoes metabolic processing primarily in: Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ivosidenib are crucial for its therapeutic efficacy: Following oral administration, ivosidenib is rapidly absorbed. The C_max following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C_max is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T_max ranges from two to three hours. A high-fat meal increases ivosidenib exposure. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ivosidenib is an important consideration for its dosing schedule: The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Ivosidenib exhibits a strong affinity for binding with plasma proteins: _In vitro_, ivosidenib is 92-96% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Ivosidenib from the body primarily occurs through: Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Ivosidenib is distributed throughout the body with a volume of distribution of: The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ivosidenib is a critical factor in determining its safe and effective dosage: The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ivosidenib exerts its therapeutic effects through: Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ivosidenib functions by: Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation _in vitro_ and _in vivo_. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Ivosidenib belongs to the class of organic compounds known as proline and derivatives. These are compounds containing proline or a derivative thereof resulting from reaction of proline at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom, classified under the direct parent group Proline and derivatives. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Ivosidenib is categorized under the following therapeutic classes: Amino Acids, Amino Acids, Peptides, and Proteins, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2C8 Inducers, Cytochrome P-450 CYP2C8 Inducers (strength unknown), Cytochrome P-450 CYP2C9 Inducers, Cytochrome P-450 CYP2C9 Inducers (strength unknown), 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 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Substrates, Enzyme Inhibitors, Isocitrate dehydrogenase-1 (IDH1) inhibitors, Isocitrate Dehydrogenase-1 Inhibitors, Moderate Risk QTc-Prolonging Agents, Narrow Therapeutic Index Drugs, OAT3/SLC22A8 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, P-glycoprotein substrates with a Narrow Therapeutic Index, 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 Ivosidenib include:

• Water Solubility:<1 mg/mL