Ivosidenib

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Isocitrate Dehydrogenase Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

FDA approved drugs -> Active ingredient

Danger

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P264, P270, P280, P301+P317, P318, P319, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Elevations in serum aminotransferase levels are common during ivosidenib therapy occurring in 15% to 20% of patients but rising above 5 times the upper limit of the normal range in only 1% to 2%. Ivosidenib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of IDH inhibitors, their potential for causing liver injury is not well defined.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ivosidenib

Ambiguous-DILI-concern

4

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

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.

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.

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.

Q2PCN8MAM6

IVOSIDENIB

Established Pharmacologic Class [EPC] - Isocitrate Dehydrogenase 1 Inhibitor

Mechanisms of Action [MoA] - Isocitrate Dehydrogenase 1 Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inducers

Mechanisms of Action [MoA] - Cytochrome P450 2C9 Inducers

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Following oral administration, ivosidenib is rapidly absorbed. The Cmax 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 Cmax 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 Tmax ranges from two to three hours. A high-fat meal increases ivosidenib exposure.

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.

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.

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.