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

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 ph...

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Published in:Cancer chemotherapy and pharmacology Vol. 85; no. 5; pp. 959 - 968
Main Authors: Fan, Bin, Dai, David, DiNardo, Courtney D., Stein, Eytan, de Botton, Stéphane, Attar, Eyal C., Liu, Hua, Liu, Guowen, Lemieux, Ian, Agresta, Samuel V., Yang, Hua
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2020
Springer Nature B.V
Subjects:
Blood cancer
Bone marrow
Cancer Research
Cholesterol
Dosage
Enzymatic activity
IDH1 protein
Isocitrate dehydrogenase
Medicine
Medicine & Public Health
Mutation
Oncology
Original Article
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Tumors
Hematologic malignancies
Pharmacokinetics
Isocitrate dehydrogenase
2-Hydroxyglutarate
Ivosidenib
ISSN:0344-5704, 1432-0843, 1432-0843
Online Access:Get full text
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Summary: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.
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ISSN:0344-5704
1432-0843
1432-0843
DOI:10.1007/s00280-020-04064-6