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

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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.

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Acknowledgements

The authors would like to thank Certara Strategic Consulting for PK and PD analysis; Samantha Abel (Valley Writing Solutions Ltd, Canterbury, UK) and Christine Ingleby, PhD, CMPP (Excel Medical Affairs, Horsham, UK) for the assistance with the preparation of this manuscript.

Funding

This work was funded by Agios Pharmaceuticals, Inc.

Author information

Authors and Affiliations

  1. Agios Pharmaceuticals, Inc., Cambridge, MA, USA

    Bin Fan, David Dai, Eyal C. Attar, Hua Liu, Guowen Liu, Ian Lemieux, Samuel V. Agresta & Hua Yang

  2. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Courtney D. DiNardo

  3. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Eytan Stein

  4. Institut Gustave Roussy, Villejuif, France

    Stéphane de Botton

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  1. Bin Fan
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  2. David Dai
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  10. Samuel V. Agresta
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Corresponding author

Correspondence to Bin Fan.

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Conflict of interest

BF, HL, GL, IL, and HY are employees of Agios Pharmaceuticals, Inc. DD, ECA, and SVA were employees of Agios at the time of the study. BF, ECA, HL, GL, IL, SVA, and HY hold stock options in Agios. ECA is a consultant to Advance Medical and is currently an employee of Aprea Therapeutics. SVA is currently an employee of Infinity Pharmaceuticals. CDD is a consultant/advisor to AbbVie, Agios, Celgene, and Notable Labs and has received honoraria from AbbVie, Agios, Celgene, Jazz, Syros, and Daiichi Sankyo. ES has stock/ownership of Auron Therapeutics; is a consultant/advisor to AbbVie, Agios, Astellas, Bayer, BioLineRx, Celgene, Daiichi Sankyo, Genentech, Novartis, Pfizer, PTC Therapeutics, and Syros; has received research funding from Agios, Amgen, Bayer, Celgene, and Syros; and has received travel expenses from Abbvie, Astellas Pharma, Celgene, Daiichi Sankyo, Novartis, and Syros. SdB is a consultant/advisor to Agios, Bayer, Carthagenetics, Celgene, FORMA Therapeutics, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier; has attended speaker’s bureau and received honoraria from AbbVie; has received honoraria and travel expenses from Agios, Carthagenetics, Celgene, FORMA Therapeutics, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier; has received honoraria from Bayer; and has received research funding from Agios.

Ethical approval

The study was conducted according to the International Conference for Harmonization Good Clinical Practice guidance and in accordance with the principles of the Declaration of Helsinki. The study was approved by independent ethics committees.

Informed consent

All patients provided written informed consent prior to participation.

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Coauthor David Dai passed away during development of this manuscript.

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Fan, B., Dai, D., DiNardo, C.D. et al. Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation. Cancer Chemother Pharmacol 85, 959–968 (2020). https://doi.org/10.1007/s00280-020-04064-6

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  • DOI: https://doi.org/10.1007/s00280-020-04064-6

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