Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies.

Abstract

Point mutations in isocitrate dehydrogenase 1 (IDH1) result in conversion of α-ketoglutarate to the oncometabolite, d-2-hydroxyglutarate (2-HG). Ivosidenib is a once daily (QD), orally available, potent, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and intensive chemotherapy-ineligible newly diagnosed AML, with a susceptible IDH1 mutation. We characterized the protein binding, metabolism, metabolites, cell permeability, and drug-drug interaction potential of ivosidenib in humans, monkeys, dogs, rats, and/or mice in in vitro experiments. In vivo pharmacokinetic (PK) profiling and assessment of drug distribution and excretion was undertaken in rats, dogs, and monkeys administered single-dose ivosidenib. The PK/pharmacodynamic (PD) relationship between ivosidenib and 2-HG was analyzed in an mIDH1 xenograft mouse model. Ivosidenib was well absorbed, showed low clearance, and moderate to long terminal half-life (5.3-18.5 hours) in rats, dogs, and monkeys. Brain to plasma exposure ratio was low (2.3%), plasma protein binding was high, and oxidative metabolism was the major elimination pathway. Ivosidenib had high cell permeability and was identified as a substrate for P-glycoprotein. There was moderate induction of cytochrome P450 (P450) enzymes CYP3A4 and CYP2B6 but minimal P450 inhibition or autoinduction. Tumor 2-HG reduction appeared to be dose- and drug-exposure-dependent. Ivosidenib showed a favorable PK profile in several animal species, along with a clear PK/PD relationship demonstrating 2-HG inhibition that translated well to patients with AML. SIGNIFICANCE STATEMENT: Ivosidenib is a mutant IDH1 (mIDH1) inhibitor approved for the treatment of certain patients with mIDH1 acute myeloid leukemia. In Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys, ivosidenib demonstrated a favorable pharmacokinetic profile, and in female BALB/c mice showed clear dose- and exposure-dependent inhibition of the oncometabolite, d-2-hydroxyglutarate, which is present at abnormal levels in mIDH1 tumors. These findings led to the further development of ivosidenib and are consistent with data from patients with mIDH1 cancers and healthy participants.

• Authors: Yue Chen, Nelamangala V Nagaraja, Bin Fan, Luke Utley, Rene M Lemieux, Janeta Popovici-Muller, Lenny Dang, Hyeryun Kim, Liping Yan, Shin-San M Su, Scott A Biller, Hua Yang
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 49 Issue 10 Pg. 870-881 (10 2021) ISSN: 1521-009X [Electronic] United States
• PMID: 34321251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antineoplastic Agents
• Glutarates
• Ketoglutaric Acids
• Pyridines
• alpha-hydroxyglutarate
• Cytochrome P-450 Enzyme System
• Isocitrate Dehydrogenase
• IDH1 protein, human
• ivosidenib
• Glycine

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics)
• Cytochrome P-450 Enzyme System (metabolism)
• Dogs
• Dose-Response Relationship, Drug
• Drug Elimination Routes
• Drug Interactions
• Glutarates (metabolism)
• Glycine (analogs & derivatives, pharmacokinetics)
• Haplorhini
• Humans
• Isocitrate Dehydrogenase (antagonists & inhibitors, genetics, metabolism)
• Ketoglutaric Acids (metabolism)
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Metabolic Clearance Rate
• Mice
• Point Mutation
• Protein Binding
• Pyridines (pharmacokinetics)
• Rats
• Xenograft Model Antitumor Assays (methods)