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.