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Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

ABSTRACT: A fixed-dose combination (FDC) of gemigliptin/metformin can improve the medication adherence in patients with type 2 diabetes mellitus (T2DM). In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin and metformin were compared between FDC and the corresponding loose combination under fasted and fed states. A two-part, randomized, open label, single-dose, two-way crossover study was conducted in healthy male subjects. Under fasted (part 1) or fed (part 2) state, 2 FDC tablets of gemigliptin/metformin sustained release (SR) 25/500 mg or loose combination with one tablet of gemigliptin 50 mg and two tablets of metformin extended release (XR) 500 mg were orally administered in each period with a 7-day washout. Serial blood samples were collected up to 48 hours to determine the drug concentration and the dipeptidyl peptidase 4 (DPP-4) activity. The concentration-time profiles of gemigliptin and metformin were similar between FDC and loose combination in both the fasted and fed states. Geometric mean ratios and 90% confidence intervals of FDC to loose combination for area under the concentration-time curve and maximum plasma concentration of gemigliptin and metformin were within the bioequivalence range (0.8-1.25) in both states. DPP-4 activity-time profiles of FDC were comparable to that of the loose combination, showing similar area under the DPP-4 inhibition-time curve and maximum DPP-4 inhibition between FDC and loose combination, regardless of the fasted or fed state. In conclusion, the PK/PD characteristics of gemigliptin and metformin were similar in FDC tablets and loose combination both in fasted and fed states. Trial Registration:ClinicalTrials.gov Identifier: NCT03355014.

SUBMITTER: Jin X

PROVIDER: S-EPMC7136079 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

Jin Xuanyou X Kim Eunwoo E Huh Ki Young KY Hwang Inyoung I Cho Joo-Youn JY Yu Kyung-Sang KS Lee SeungHwan S

Translational and clinical pharmacology 20200330 1

A fixed-dose combination (FDC) of gemigliptin/metformin can improve the medication adherence in patients with type 2 diabetes mellitus (T2DM). In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin and metformin were compared between FDC and the corresponding loose combination under fasted and fed states. A two-part, randomized, open label, single-dose, two-way crossover study was conducted in healthy male subjects. Under fasted (part 1) or fed (part 2) state, 2 ...[more]

PMID: 32274380

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Project description:BackgroundIn type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets.MethodsA randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study.ResultsThe plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated.ConclusionThe PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin sustained release can be a convenient therapeutic option in patients with type 2 diabetes mellitus requiring a combination approach.

Project description:PurposeA fixed-dose combination (FDC) of gemigliptin/rosuvastatin 50/20 mg as a monolayer tablet has been used to treat patients with both type 2 diabetes mellitus and dyslipidemia. To improve the stability of the FDC, a new FDC formulation as a bilayer tablet was developed. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the FDC of gemigliptin/rosuvastatin 50/20 mg between the newly developed bilayer tablet and the approved monolayer tablet in healthy subjects.Materials and methodsA randomized, open-label, single-dose, two-treatment, two-way crossover study was conducted. Subjects received a single dose of the FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet or the monolayer tablet in each period with a 7-day washout. For PK and PD analyses, serial blood samples were collected up to 72 hours after dosing to determine plasma concentrations of gemigliptin, its active metabolite LC15-0636 and rosuvastatin, and plasma dipeptidyl peptidase-4 (DPP-4) activity. PK and PD parameters were calculated using non-compartmental methods and compared between the two formulations.ResultsA total of 48 healthy subjects were randomized, and 45 subjects completed the study. The concentration-time profiles of gemigliptin, LC15-0636 and rosuvastatin were comparable between the two formulations. All geometric mean ratios (90% confidence intervals) of the bilayer tablet to the monolayer tablet for maximum plasma concentration and area under concentration-time curve from 0 to last measurable time point of the three compounds fulfilled the bioequivalence criteria of 0.80-1.25. Likewise, area under plasma DPP-4 activity inhibition from baseline-time curve from 0 to last measurable time point and maximum inhibition of plasma DPP-4 activity were similar between the two formulations.ConclusionThe FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet showed equivalent PK and PD properties with the FDC of gemigliptin/rosuvastatin 50/20 mg as the monolayer tablet in healthy subjects. These results suggest that the newly developed bilayer tablet can become an alternative formulation to the commercially available monolayer tablet.

Dataset Information

Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

Publications

Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

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