A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects

Abstract

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.

Pharmacokinetic and Pharmacodynamic Comparison of Two Formulations of a Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg: A Randomized, Open-Label, Single-Dose, Two-Way Crossover Study

“…Because the degree of inhibition of DPP-4 activity is a direct PD biomarker of DPP-4 inhibitors, 14 , 22 , 23 this study measured the plasma DPP-4 activity to evaluate the PDs of gemigliptin in the two formulations, and similar values for AUEC last and I max were observed regardless of the formulation. Recently, several studies showed that the degree of inhibition of DPP-4 activity after administration of DPP-4 inhibitors was comparable in normoglycemic and diabetic subjects.…”

Pharmacokinetic Equivalence of the High Dose Strength Fixed-Dose Combination Tablet of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects

“…Furthermore, these results are consistent with a similarly designed study comparing two tablets of the FDC (gemigliptin/metformin SR 25/500 mg), collectively, 50 mg and 1,000 mg, and the separate tablets. 16 The reference tablets used in this study were the same as those used in the pivotal safety and efficacy studies for each agent, thus providing a direct link with the FDC tablet. Additionally, the peak and total exposures of LC15-0636 (metabolite of gemigliptin) were similar in both the FDC tablet and the individual tablets, further supporting the interchangeability of the FDC tablet and the individual tablets (data not shown).…”

“…A recent study reported that the pharmacokinetics, pharmacodynamics, and tolerability profile of gemigliptin and metformin were comparable in healthy subjects who were administered a FDC (gemigliptin/metformin SR 25 mg/500 mg) and co-administered two individual tablets. 16 The objective of this study was to establish pharmacokinetic equivalence between the higher dose strength FDC tablet (gemigliptin/metformin SR 50/1,000 mg) and the corresponding co-administered doses of gemigliptin and metformin as individual tablets in healthy male volunteers.…”

A systematic and critical review on bioanalytical method validation using the example of simultaneous quantitation of antidiabetic agents in blood

“…We observed two reasons for the absence of validation data in the articles: the study was performed before the guidelines had been published [53][54][55][56][57][58][59][60][61][62][63][64][65][66]; and the study focus was on method development and validation was not addressed [67][68][69][70][71][72]. Other reasons for excluding articles were: non-simultaneous method [74][75][76][77], inappropriate sample preparation [78,79], literature review [80], animal plasma sample [81], language in non-Roman characters [82][83][84], validation of only one analyte [85,86], and pharmacokinetic studies (PK) that used a previously developed and validated method [87][88][89][90][91][92][93][94][95][96][97].…”