Pharmacokinetics, absorption, metabolism, and excretion of [14C]ivosidenib (AG-120) in healthy male subjects

• Published in: Cancer chemotherapy and pharmacology Vol. 83; no. 5; pp. 837 - 848
• Main Authors: Prakash, Chandra, Fan, Bin, Altaf, Syed, Agresta, Sam, Liu, Hua, Yang, Hua
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2019; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Area Under Curve; Blood levels; Cancer Research; Carbon Radioisotopes; Chromatography, Liquid; CYP2D6 protein; Cytochrome P450; Erythrocytes; Excretion; Feces; Feces - chemistry; Genotypes; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - blood; Glycine - pharmacokinetics; Glycine - urine; Healthy Volunteers; High-performance liquid chromatography; Humans; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - antagonists & inhibitors; Limit of Detection; Male; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Metabolism; Metabolites; Middle Aged; Oncology; Oral administration; Original Article; Pharmacokinetics; Pharmacology/Toxicology; Pyridines - administration & dosage; Pyridines - blood; Pyridines - pharmacokinetics; Pyridines - urine; Radioactivity; Tandem Mass Spectrometry; Tissue Distribution; Urine; Isocitrate dehydrogenase-1 (IDH1); Excretion; Absorption; Ivosidenib (AG-120); Metabolites; Cytochrome P450; Metabolism; LC–MS/MS
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03793-7

Purpose Pharmacokinetics, absorption, metabolism, and excretion of ivosidenib, a mutant isocitrate dehydrogenase-1 inhibitor, were determined in healthy male subjects. Methods In this open-label phase I study, a single dose of [ 14 C]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. Results Ivosidenib was readily absorbed and slowly eliminated from plasma. Median T max of both unchanged ivosidenib and radioactivity in plasma was 4 h. Plasma t ½ values for total radioactivity and ivosidenib were 71.7 and 53.4 h, respectively. The mean AUC 0–72 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 [ 14 C]ivosidenib accounted for 67.4% of the administered radioactivity in feces. Only [ 14 C]ivosidenib was detected in plasma, representing 92.4% of the total plasma radioactivity. Thirteen metabolites were structurally identified in excreta. Conclusion 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.