Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation

Cancer Chemother Pharmacol. 2020 May;85(5):959-968. doi: 10.1007/s00280-020-04064-6. Epub 2020 Apr 15.


Purpose: Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study ( NCT02074839).

Methods: Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity.

Results: Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib.

Conclusions: Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation.

Clinical trial registration: NCT02074839.

Keywords: 2-Hydroxyglutarate; Hematologic malignancies; Isocitrate dehydrogenase; Ivosidenib; Pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Monitoring / methods
  • Female
  • Glycine / administration & dosage
  • Glycine / adverse effects
  • Glycine / analogs & derivatives*
  • Glycine / pharmacokinetics
  • Hematologic Neoplasms* / drug therapy
  • Hematologic Neoplasms* / genetics
  • Hematologic Neoplasms* / pathology
  • Humans
  • Isocitrate Dehydrogenase* / antagonists & inhibitors
  • Isocitrate Dehydrogenase* / genetics
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Maximum Tolerated Dose
  • Mutation
  • Neoplasm Staging
  • Pyridines* / administration & dosage
  • Pyridines* / adverse effects
  • Pyridines* / pharmacokinetics
  • Treatment Outcome


  • Antineoplastic Agents
  • Pyridines
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • ivosidenib
  • Glycine

Associated data