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

• Published in: Clinical therapeutics Vol. 33; no. 11; pp. 1809 - 1818
• Main Authors: Shin, Kwang-Hee, MS, Kim, Sung Eun, BS, Yoon, Seo Hyun, PhD, Cho, Joo-Youn, PhD, Jang, In-Jin, MD, PhD, Shin, Sang-Goo, MD, PhD, Yu, Kyung-Sang, MD, PhD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.11.2011; Elsevier; Elsevier Limited
• Subjects: Adult; Amaryl ®-Mex SR 1/500 mg; Biological and medical sciences; Biomedical research; Chromatography, Liquid; Clinical trials; Cross-Over Studies; Delayed-Action Preparations; Diabetes; Drug Combinations; Drug dosages; fixed-dose combination; glimepiride; Half-Life; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Insulin; Internal Medicine; Male; Medical Education; Medical sciences; metformin; Metformin - administration & dosage; Metformin - pharmacokinetics; Middle Aged; pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Plasma; Reference Values; Sulfonylurea Compounds - administration & dosage; Sulfonylurea Compounds - pharmacokinetics; sustained-release; Tandem Mass Spectrometry; Asia; Korea; South Korea; pharmacokinetics; Amaryl ®-Mex SR 1/500 mg; metformin; fixed-dose combination; sustained-release; glimepiride; Human; Glimepiride; Drug combination; Healthy subject; Controlled release form; Mex SR 1/500 mg; Amaryl; Crossover study; Hypoglycemic agent; Randomization; Biguanides; Treatment; Sulfonamides; Formulation; Sulfonylureas; Dosage form; Tablet; Metformin; Pharmacokinetics; Comparative study
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2011.10.003

Abstract 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 Cmax and AUC0–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 Cmax and AUC0–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. ClinicalTrials.gov identifier: NCT00934323.