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Research ArticleArticle

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

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 and Hua Yang
Drug Metabolism and Disposition October 2021, 49 (10) 870-881; DOI: https://doi.org/10.1124/dmd.120.000234
Yue Chen
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Nelamangala V. Nagaraja
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Bin Fan
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Luke Utley
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Rene M. Lemieux
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Janeta Popovici-Muller
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Lenny Dang
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Hyeryun Kim
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Liping Yan
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Shin-San M. Su
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Scott A. Biller
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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Hua Yang
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, Cambridge, Massachusetts (L.U.); Faze Medicines, Inc., Cambridge, Massachusetts (R.M.L.); Rectify Pharmaceuticals, Cambridge, Massachusetts (J.P.-M.); Volastra Therapeutics, Inc., New York, New York (S.-S.M.S.); and Disc Medicine, Cambridge, Massachusetts (H.Y.)
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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.

Footnotes

    • Received August 28, 2021.
    • Accepted July 22, 2021.
  • This work was supported by Agios Pharmaceuticals, Inc.

  • Y.C., L.D., H.K., and S.A.B.: employee and stock-holder of Agios Pharmaceuticals, Inc. N.V.N. was an employee and stock-holder of Agios Pharmaceuticals, Inc. at the time of submission of this work and is currently an employee of Servier Pharmaceuticals LLC. B.F., L.U., R.M.L., J.P.-M., S.-S.M.S., and H.Y.: employee and stock-holder of Agios Pharmaceuticals, Inc. at the time of this work. L.Y.: employee of ChemPartner, a vendor contracted to perform research for Agios Pharmaceuticals, Inc.

  • https://doi.org/10.1124/dmd.120.000234.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (10)
Drug Metabolism and Disposition
Vol. 49, Issue 10
1 Oct 2021
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Research ArticleArticle

Preclinical Drug Metabolism and PK Profile of Ivosidenib

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 and Hua Yang
Drug Metabolism and Disposition October 1, 2021, 49 (10) 870-881; DOI: https://doi.org/10.1124/dmd.120.000234

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Research ArticleArticle

Preclinical Drug Metabolism and PK Profile of Ivosidenib

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 and Hua Yang
Drug Metabolism and Disposition October 1, 2021, 49 (10) 870-881; DOI: https://doi.org/10.1124/dmd.120.000234
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