Pharmacokinetics, absorption, metabolism, and excretion of [14C]ivosidenib (AG-120) in healthy male subjects
Pharmacokinetics, absorption, metabolism, and excretion of ivosidenib, a mutant isocitrate dehydrogenase-1 inhibitor, were determined in healthy male subjects.
In this open-label phase I study, a single dose of [14C]ivosidenib (500 mg, 200 µCi/subject) was orally administered to eight subjects (CYP2D6 extensive, intermediate, or poor metabolizers) under fasted conditions. Blood, plasma, urine, and fecal samples were assayed for radioactivity and profiled for metabolites. Ivosidenib plasma concentrations were determined using LC–MS/MS. Metabolites were separated using reverse-phase HPLC and analyzed using high-resolution LC–MS and LC–MS/MS.
Ivosidenib was readily absorbed and slowly eliminated from plasma. Median Tmax of both unchanged ivosidenib and radioactivity in plasma was 4 h. Plasma t½ values for total radioactivity and ivosidenib were 71.7 and 53.4 h, respectively. The mean AUC0–72 blood-to-plasma total radioactivity concentration ratio was 0.565, indicating minimal partitioning to red blood cells. CYP2D6 genotype had no effect on ivosidenib exposure. The mean recovery of radioactivity in excreta was 94.3% over 360 h post-dose; the majority was excreted in feces (77.4 ± 9.62%) with a low percentage recovered in urine (16.9 ± 5.62%), suggesting fecal excretion is the primary route of elimination. Unchanged [14C]ivosidenib accounted for 67.4% of the administered radioactivity in feces. Only [14C]ivosidenib was detected in plasma, representing 92.4% of the total plasma radioactivity. Thirteen metabolites were structurally identified in excreta.
Ivosidenib was well-absorbed, slowly metabolized to multiple oxidative metabolites, and eliminated by fecal excretion, with no CYP2D6 effect observed. Unchanged ivosidenib was the only circulating species in plasma.
KeywordsAbsorption Metabolism Excretion Isocitrate dehydrogenase-1 (IDH1) Ivosidenib (AG-120) Metabolites LC–MS/MS Cytochrome P450
The authors would like to acknowledge the contributions of Covance Clinical for conducting the study and Covance Drug Metabolism and Pharmacokinetics Department for ADME profiling. We would like to also thank Gary Conner, Camelia Gliser, Shijie Zhang, and Huayu Xiong (Agios) for their help in conducting the study; and Christine Ingleby Ph.D. (of Excel Medical Affairs, Horsham, UK, funded by Agios) and Allyson Bower (Agios) for editorial assistance with the manuscript. We would also like to thank the volunteers who participated in the study.
All authors performed data analysis and interpretation, as well as manuscript writing, review, and approval.
This study was supported financially by Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
Compliance with ethical standards
Conflict of interest
All authors were paid employees of Agios Pharmaceuticals, Inc., Cambridge, MA, USA at the time of the study.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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