Evaluation of Pharmacokinetic Drug Interactions Between Gemigliptin (Dipeptidylpeptidase-4 Inhibitor) and Glimepiride (Sulfonylurea) in Healthy Volunteers

Abstract

PurposeGemigliptin is approved for the treatment of type II diabetes mellitus. Sulfonylureas are commonly used in combination with other antidiabetic drugs to improve glycemic control. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of gemigliptin and glimepiride combination therapy compared with those of monotherapies.MethodsA randomized, open-label, crossover study was performed on healthy Korean male volunteers. Each subject received the following treatments (A and B) with a 7-day washout period: treatment A consisted of gemigliptin 50 mg once daily administered orally for 6 days, followed by concomitant oral dosing of glimepiride 4 mg and gemigliptin 50 mg on day 7; treatment B consisted of a single dose of glimepiride 4 mg. Blood samples were collected up to 24-h postdose on day 6 (gemigliptin) and day 7 (gemigliptin and glimepiride) following treatment A, and on day 1 (glimepiride) following treatment B. Concentrations of gemigliptin, glimepiride, and metabolites were determined using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). Safety assessments were performed throughout the study.ResultsTwenty-three subjects completed the study. The geometric mean ratios (GMRs) of Cmax,ss and AUCτ,ss for gemigliptin were 1.0097 [90 % confidence interval (CI) 0.924–1.103] and 0.9997 (90 % CI 0.976–1.024), respectively. For glimepiride, the GMRs of Cmax and AUClast were 1.031 (90 % CI 0.908–1.172) and 0.995 (90 % CI 0.902–1.097), respectively. Both combination and monotherapy were well tolerated, and no serious adverse events were reported.ConclusionGemigliptin and glimepiride did not alter the pharmacokinetic properties of each other when they were co-administered in healthy volunteers, and were generally tolerated.

<p>Pharmacokinetic/Pharmacodynamic Interactions Between Evogliptin and Glimepiride in Healthy Male Subjects</p>

“…these results were similar to those of studies that evaluated PK interactions between glimepiride and other DPP-4 inhibitors including teneligliptin and gemigliptin. 20,21 Evogliptin is mainly metabolized by CYP3A, whereas glimepiride might be a potential CYP3A4 inhibitor as evinced from the increased plasma concentration of sildenafil that is mainly metabolized by CYP3A4 in rats. 8,22 Additionally, evogliptin did not significantly change the PK properties of glimepiride that is mainly metabolized by CYP2C9, ie, evogliptin did not induce or inhibit CYP enzymes (unpublished in-house data).…”

“…In addition, these results were similar to those of studies that evaluated PK interactions between glimepiride and other DPP-4 inhibitors including teneligliptin and gemigliptin. 20 , 21 …”

Gemigliptin: Newer promising gliptin for type 2 diabetes mellitus

“…Studies also revealed that gemigliptin did not alter the pharmacokinetics of most commonly used antidiabetic agents (metformin, glimepiride, and pioglitazone), antihypertensives, and lipid lowering agents. [ 18 19 20 21 ] Ketoconazole, a CYP3A4 inhibitor, moderately increased gemigliptin exposure while it was reduced when coadministered with rifampicin, a CYP3A4 inducer. [ 22 ]…”

Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus

“…In several drug-drug interaction studies, gemigliptin did not meaningfully alter pharmacokinetics of co-medications frequently used to treat T2DM, such as antidiabetic agents (metformin, pioglitazone, and glimepiride), and antihypertensive and lipid-lowering agents (irbesartan and rosuvastatin) [ 30 31 32 33 ]. Although co-administration of ketoconazole, a potent inhibitors of CYP3A4, resulted in a moderate increase in gemigliptin exposure (1.9-fold as total active moiety of gemigliptin), no dosage adjustment should be required when gemigliptin is co-administered with ketoconazole.…”