Pharmacokinetics, Bioavailability Study in Rats, and Tissue Distribution in Mice of Enasidenib by UPLC-MS/MS

Enasidenib is a first-in-class, orally available inhibitor of mutant IDH2 and was approved by the US Food and Drug Administration (FDA) as a treatment of adult patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Studies of enasidenib about pharmacokinetics and bioavailability after oral and intravenous administration and tissue distribution in animal model have not been reported. This limits basic research regarding this mutant IDH2 inhibitor drug. The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was used to determine the enasidenib in rat plasma, and mouse tissues with dacomitinib used as internal standard (IS). The mobile phase, which is acetonitrile solution containing 0.1 % formic acid, was applied in chromatographic separation on a CORTECS C18 column (2.1 x 50 mm, 1.6 mu m) by gradient elution. To quantify the enasidenib, positive-electrospray ionization mode was used for multiple reaction monitoring (MRM). Target fragment ions were 474.57 -> 456.64 m/z for enasidenib and 471.21 -> 128.1 m/z IS. Calibration curve has a lower limit of quantification (LLOQ) of at least 1 ng/mL and was linear within 2-2000 ng/mL for enasidenib in the rat plasma and mouse tissues. Inter-day and intra-day accuracy were within 87.53 to 105.58% with precision of the method both less than 15%. The mean recovery value of enasidenib was > 99.53%. Our study demonstrated that although blood brain barrier existed, there were still rapid absorption and wide distribution of enasidenib in various tissues. The order of enasidenib concentration level observed in liver was kidney, spleen, lung, heart in the sequence of descending.