Your browser doesn't support javascript.
loading
Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies.
Chen, Yue; Nagaraja, Nelamangala V; Fan, Bin; Utley, Luke; Lemieux, Rene M; Popovici-Muller, Janeta; Dang, Lenny; Kim, Hyeryun; Yan, Liping; Su, Shin-San M; Biller, Scott A; Yang, Hua.
Affiliation
  • Chen Y; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Nagaraja NV; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Fan B; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Utley L; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Lemieux RM; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Popovici-Muller J; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Dang L; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Kim H; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Yan L; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Su SM; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Biller SA; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
  • Yang H; Agios Pharmaceuticals, Inc., Cambridge, Massachusetts (Y.C., N.V.N., B.F., L.U., R.M.L., J.P.-M., L.D., H.K., S.-S.M.S., S.A.B., H.Y.); ChemPartner, Shanghai, China (L.Y.); Servier Pharmaceuticals LLC, Boston, Massachusetts (N.V.N.); KLUS Pharma, Cranbury, New Jersey (B.F.); Ribon Therapeutics, Camb
Drug Metab Dispos ; 49(10): 870-881, 2021 10.
Article in En | MEDLINE | ID: mdl-34321251
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Leukemia, Myeloid, Acute / Glycine / Isocitrate Dehydrogenase Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2021 Document type: Article Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Leukemia, Myeloid, Acute / Glycine / Isocitrate Dehydrogenase Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2021 Document type: Article Publication country: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA