Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects

Abstract

The aim of this study was to assess and compare the pharmacokinetics (PK) and safety of Enasidenib in healthy adult male Japanese subjects to healthy adult male Caucasian subjects. This was a phase 1, single dose study to evaluate the PK and safety of Enasidenib in healthy adult male Japanese subjects relative to healthy adult male Caucasian subjects. A total of 62 subjects (31 Japanese and 31 Caucasian) were enrolled into three dose cohorts (single doses of 50 mg, 100 mg, or 300 mg Enasidenib). Blood samples for PK assessment were collected up to 672 hours postdose. Safety was evaluated throughout the study. In the present study, we found that PK exposures of Enasidenib and its metabolite AGI‐16903 for Caucasian and Japanese subjects were comparable at the 50, 100, and 300 mg dose levels, demonstrated by that the 90% confidence intervals (CIs) of geometric mean ratios for AUCs and C max between these two populations generally contained 100% from all three treatment cohorts. In conclusion, PK exposures of Enasidenib and its metabolite AGI‐16903 for Caucasians and Japanese subjects were comparable and Enasidenib was safe and well tolerated with no apparent differences between Japanese and Caucasian subjects when administered as single oral doses of 50 mg, 100 mg, and 300 mg.

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

“…The % remained was 94.7 and 74.4 in mice liver microsomes and 97.6 and 80.7 in human liver microsomes, for enasidenib and AGI-16903, respectively at the end of 30 min incubation time. These results clearly indicate that the percent remained for enasidenib was higher than AGI-16903 in both matrices and support for the higher exposure for enasidenib in mice (present study) and in humans as reported by Li et al [8].…”

“…We have also digitalized using DigitizeIt (version 2.0.0; accessed on 27 July 2019 available at https://www.digitizeit.de) the reported plots of enasidenib and AGI-16903 in healthy Caucasian and Japanese subjects post administration 100 mg oral dose of enasidenib [8] and found that enasidenib and AGI-16903 reaches the reported LLOQ (1.01 ng/mL) by 14 th and 10 th day, respectively which is contrary to the reported (up to 28 th day). This indicates that the method used by Li et al [8] for quantitation of enasidenib and AGI-16903 may not be sensitive enough to determine the plasma concentrations of enasidenib and AGI-16903 till the reported time despite using higher volume of plasma (100 µL).…”

“…Application of the validated method was shown in a pharmacokinetic study in mice. multaneous quantitation of enasidenib and AGI-16903 [8]. The first LC-MS/MS method reported by Pang et al (2018) was in rat plasma with a linearity range of 2-500 ng/mL.…”

“…Subsequently, Dittakavi et al (2018) reported [7] a mice dried blood spot (DBS) method for quantitation of enasidenib on LC-MS/MS with higher sensitivity over the previously published method along with addressing the demerits of previously published method [6]. Recently, Li et al [8] reported simultaneous quantitation of enasidenib and AGI-16903 in Japanese and Caucasian subjects plasma as part of Phase I study to evaluate the pharmacokinetics and safety in these subjects. The reported LLOQ was 1.0 ng/mL (both the analytes) using 100 µL plasma.…”

Development and Validation of UPLC-MS/MS Method for Determination of Enasidenib in Rat Plasma and Its Pharmacokinetic Application

“…Now, enasidenib has provided a new treatment approach for patients with refractory AML with recurrence and IDH2 mutations [11][12][13]. However, there are only three papers which reported the pharmacokinetic profiles of enasidenib [14][15][16][17]. Among them, only one LC-MS/MS method has been published to determine the concentration of enasidenib in biological media in detail, which has long analytical time, low sensitivity, and complex sample preparation process [16].…”