Inhibitory effects of voriconazole, itraconazole and fluconazole on the pharmacokinetic profiles of ivosidenib in rats by UHPLC-MS/MS

Ivosidenib, as an oral mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, was awarded approval in the USA for the targeted therapy of relapsed or refractory acute myeloid leukemia (AML) in adult patients, who also had a susceptible enzyme to mIDH1. The aim of our present study was to develop and validate an accurate and fast assay based on the ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique for the quantification of ivosidenib in plasma and to investigate the possible effects of different CYP3A4 inhibitors (voriconazole, itraconazole and fluconazole) on ivosidenib metabolism in rats. After the fast protein crash with acetonitrile, chromatographic separation of ivosidenib and erlotinib (used as the internal standard in this experiment, IS) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column, and detection of the analyte was also performed using a Xevo TQ-S triple quadrupole tandem mass spectrometer in the positive ion electrospray ionization (ESI) interface. The assay showed enough linearity over a 0.5−6000 ng/mL calibration range. The application of the validated bioanalytical method based on the UHPLC-MS/MS technique was further successfully exhibited in an animal study of the drug-drug interaction between ivosidenib (50 mg/kg) and voriconazole (20 mg/kg)/itraconazole (20 mg/kg)/fluconazole (20 mg/kg) in rats. Voriconazole, itraconazole and fluconazole increased the exposure of ivosidenib in plasma by different degrees and also had a potential inhibitory effect on the metabolism of ivosidenib. Thus, a dose reduction or interruption of ivosidenib may be important to guide the practice of clinical medicine.