Pharmacokinetic comparison of a new sustained-release formulation of glimepiride/metformin 1/500 mg combination tablet and a sustained-release formulation of glimepiride/metformin 2/500 mg combination tablet in healthy Korean male volunteers: a randomized, 2-sequence, 2-period, 2-treatment crossover study.
BACKGROUND
The combination of glimepiride and metformin is used for glycemic control in patients with diabetes mellitus. A fixed-dose combination of glimepiride/metformin 2/500 mg slow-release (SR) formulation was developed to improve compliance in polymedicated patients. To accommodate the various dosing regimens of glimepiride, a glimepiride/metformin 1/500 mg SR tablet was also developed.


OBJECTIVE
The goal of this study was to compare the pharmacokinetic properties of SR fixed-dose combinations of glimepiride/metformin 2/500 mg and the newly developed glimepiride/metformin 1/500 mg formulation to meet the regulatory requirements for marketing in Korea.


METHODS
An open-label, randomized, 2-treatment, 2-period, 2-sequence crossover study was conducted with healthy male volunteers. Eligible subjects were randomly assigned to receive a single dose of glimepiride/metformin 1/500 mg SR (test) or glimepiride/metformin 2/500 mg SR (reference) followed by a 1-week washout period and then administration of the alternate treatment. Serial blood samples were collected immediately before and after dosing for 30 hours, and plasma concentrations were determined by using LC-MS/MS with validated methods. Adverse events were assessed by subjects' self-report and interviews addressing general health-related issues. Safety profiles were evaluated throughout the study.


RESULTS
Thirty-three subjects were enrolled (mean [SD] age: 27.9 [4.95] years [range, 21-40 years]). Safety profiles were assessed for all 32 subjects who were administered the study drugs, and pharmacokinetic characteristics were evaluated in the 30 subjects who completed the study. The geometric mean ratios (90% CIs) of test to reference for the dose-normalized C(max) and AUC(0-last) of glimepiride were 0.98 (0.90-1.07) and 1.06 (0.98-1.14), respectively. In the case of metformin, the geometric mean ratios (90% CIs) of test to reference for C(max) and AUC(0-last) were 1.06 (0.98-1.15) and 1.04 (0.97-1.12), respectively. Nine adverse events were reported. Among them, loose stool, abdominal pain, and headache were considered to be likely related to the study drug. All reported adverse events were mild in intensity.


CONCLUSIONS
Dose-proportional characteristics of glimepiride and comparable pharmacokinetic properties of metformin were observed between the SR fixed-dose combinations of glimepiride/metformin 1/500 mg and 2/500 mg. A single dose of either treatment was well tolerated, and the safety profiles of the 2 treatments were comparable in this small, selected all-male group of healthy Korean volunteers.
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Kwang-Hee
KH
Shin
Sung Eun
SE
Kim
Seo Hyun
SH
Yoon
Joo-Youn
JY
Cho
In-Jin
IJ
Jang
Sang-Goo
SG
Shin
Kyung-Sang
KS
Yu
D000328:Adult; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D012016:Reference Values; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
D003692:Delayed-Action Preparations; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D008687:Metformin