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

Bin Fan, David Dai, Courtney D. DiNardo, Eytan Stein, Stéphane de Botton, Eyal C. Attar, Hua Liu, Guowen Liu, Ian Lemieux, Samuel V. Agresta, Hua Yang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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 (ClinicalTrials.gov 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: ClinicalTrials.gov NCT02074839.

Original languageEnglish (US)
Pages (from-to)959-968
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume85
Issue number5
DOIs
StatePublished - May 1 2020

Keywords

  • 2-Hydroxyglutarate
  • Hematologic malignancies
  • Isocitrate dehydrogenase
  • Ivosidenib
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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