Pharmacokinetic analysis
Liquid chromatography with tandem mass spectrometry was used to analyze
plasma evogliptin, evogliptin M7, evogliptin M8, glimepiride, and
glimepiride M1 and urine evogliptin concentrations. In blank human
plasma and urine, no interference of endogenous compounds was observed.
The calibration curves of undiluted samples were linear over the range
of concentration from 0.1 μg/L to 60 μg/L for plasma evogliptin; from 10
ng/L to 10000 ng/L for plasma evogliptin M7 and evogliptin M8; from 5
μg/L to 2000 μg/L for plasma glimepiride; from 0.5 μg/L to 500 μg/L for
plasma glimepiride M1; from 5 to 50000 μg/L for urine evogliptin. The
within-run accuracy and precision were 97.2 - 105.5 % and 0.8 - 7.2 %
for plasma evogliptin; 94.9 - 103.2 % and 0.2 - 6.9 % for plasma
evogliptin M7; 86.7 -106.3 % and 0.1 - 11.2 % for plasma evogliptin
M8; and for plasma glimepiride; and for plasma glimepiride M1; 97.5 -
104.6 % and 3.3 - 6.5 % for urine evogliptin.
The individual PK parameters were determined via noncompartmental
methods using Phoenix
WinNonlin® software version 8.0 (Certara, Princeton,
NJ, USA). The maximum concentration at steady-state
(Cmax,ss) and Tmax at steady state
(Tmax,ss) were determined by observing the plasma
concentration-time data. The half-life at steady state
(T1/2,ss) was determined by fitting a linear regression
for evogliptin, evogliptin M7, evogliptin M8, glimepiride, and
glimepiride M1. The area under the plasma concentration-time curve over
dosing interval at steady-state (AUCτ,ss) and the total
apparent clearance at steady-state (CLss) were
determined using the linear-log trapezoidal method.
The fraction excreted unchanged in urine over dosing interval at
steady-state (feτ,ss) was determined by dividing the
amount excreted unchanged in urine over dosing interval at steady-state
(Aeτ,ss) by the total dose given on the day of urine
collection. The renal clearance at steady-state (CLR,ss)
was determined as Aeτ,ss divided by the
AUCτ,ss for evogliptin.