Pharmacokinetic/Pharmacodynamic Evaluation of Ivosidenib or Enasidenib Combined With Intensive Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed IDH1/2-Mutant Acute Myeloid Leukemia
Bin Fan, Yue Chen, Feng Yin, Lei Hua, Caroline Almon, Salah Nabhan, Michael Cooper, Hua Yang, Mohammad Hossain, Bin Fan, Yue Chen, Feng Yin, Lei Hua, Caroline Almon, Salah Nabhan, Michael Cooper, Hua Yang, Mohammad Hossain
Abstract
Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.
Keywords: AML; PK/PD; enasidenib; isocitrate dehydrogenase; ivosidenib.
Conflict of interest statement
B.F., F.Y., L.H., C.A., S.N., M.C., H.Y., and M.H. were employees of and held stock/ownership interests in Agios at the time of this study. M.C. and M.H. are employees of Servier. Y.C. is an employee of and holds stock/ownership interests in Agios.
© 2022 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
Figures
References
- Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27(4): 599‐608.
- Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2): 272‐281.
- Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8): 765‐773.
- Cancer Genome Atlas Research Network, Brat DJ, Verhaak RGW, et al. Comprehensive, integrative genomic analysis of diffuse lower‐grade gliomas. N Engl J Med. 2015;372(26):2481‐2498.
- Dang L, White DW, Gross S, et al. Cancer‐associated IDH1 mutations produce 2‐hydroxyglutarate. Nature. 2009;462(7274): 739‐744.
- Ward PS, Patel J, Wise DR, et al. The common feature of leukemia‐associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha‐ketoglutarate to 2‐hydroxyglutarate. Cancer Cell. 2010;17(3):225‐234.
- Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474‐478.
- Xu W, Yang H, Liu Y, et al. Oncometabolite 2‐hydroxyglutarate is a competitive inhibitor of α‐ketoglutarate‐dependent dioxygenases. Cancer Cell. 2011;19(1):17‐30.
- Popovici‐Muller J, Lemieux RM, Artin E, et al. Discovery of AG‐120 (ivosidenib): a first‐in‐class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett. 2018;9(4):300‐305.
- Yen K, Travins J, Wang F, et al. AG‐221, a first‐in‐class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017;7(5):478‐493.
- DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1‐mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386‐2398.
- Fan B, Dai D, DiNardo CD, et al. Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation. Cancer Chemother Pharmacol. 2020;85(5):959‐968.
- Fan B, Mellinghoff IK, Wen PY, et al. Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Invest New Drugs. 2020;38(2):433‐444.
- Stein EM, DiNardo CD, Fathi AT, et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood. 2021;137(13): 1792‐1803.
- Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722‐731.
- Dai D, Yang H, Nabhan S, et al. Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects. Eur J Clin Pharmacol. 2019;75(8):1099‐1108.
- Prakash C, Fan B, Altaf S, Agresta S, Liu H, Yang H. Pharmacokinetics, absorption, metabolism, and excretion of [14C]ivosidenib (AG‐120) in healthy male subjects. Cancer Chemother Pharmacol. 2019;83(5):837‐848.
- Li Y, Liu L, Gomez D, et al. Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects. Pharmacol Res Perspect. 2018;6(6):e00436.
- Tong Z, Atsriku C, Yerramilli U, et al. Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase‐2 inhibitor enasidenib in rats and humans. Xenobiotica. 2019;49(2):200‐210.
Source: PubMed