DISCUSSION
According to in vitro studies, evogliptin does not induce nor
inhibit CYP enzymes, while its metabolism is primarily mediated by
CYP3A4 to form metabolites with unknown activity (M7 and
M8).[10,
18] On the other hand, pioglitazone is
extensively metabolized, mainly by CYP2C8, CYP3A4 and CYP2C9 to form
active metabolites (M3 and M4).[13,
14] No clinically significant CYP
enzyme induction nor inhibition by pioglitazone has been identifiedin vivo. [13,
14] Since the elimination pathways of
evogliptin and pioglitazone shows little possibility to affect each
other, pharmacokinetic interaction of the two drug is unlikely to occur,
as the result of current study suggests.
For pioglitazone, total pioglitazone (pioglitazone, M3 and M4)
concentration were also similar between treatment groups. GMR (90% CI)
of EVO+PIO to PIO for Cmax,ss and
AUCτ,ss were 106.95 (102.16 – 111.97) and 106.38
(101.76 – 111.22), respectively, and contained within conventional
limits of bioequivalence.
Changes of glucose and insulin level during OGTT were measured as
pharmacodynamic parameters at baseline and each treatment period.
Reduction of glucose level after combination therapy compared to
baseline, expressed as maximum concentrations (Gmax,ss,
Emax,ss) and area under-curves
(AUGCτ,ss, AUECτ,ss), was not superior
compared to administration of each drug alone. Since combination of
other DPP-4s (alogliptin, vildagliptin and linagliptin) with
pioglitazone have led to greater efficacy (HbA1C reduction) than each
medication alone in T2DM patients, a greater reduction of glucose level
was expected.[19-21] The discrepancy
could be attributable to the study design which includes healthy
subjects with unimpaired glucose tolerance. To verify pharmacodynamic
interaction and clinical implication of combination of evogliptin and
pioglitazone, further study with larger sample size of T2DM patients can
be considered.
Despite insulinotropic effect of DPP-4 inhibitor, postprandial insulin
level at all three treatment periods were lower than baseline. Similar
insulin profiles were obtained from previous studies which administered
evogliptin and other drugs of same class including sitagliptin to
healthy subjects.[8] In case of
sitagliptin, insulinotropic effect was observed in DM patients after
administration of the same dose that did not produce significant change
of insulin level in healthy
subjects.[22,
23] Therefore, these pharmacodynamic
results in healthy volunteers should not be used alone to determine the
efficacy of evogliptin.