Comparison of the bioavailability and tolerability of fixed-dose combination glimepiride/metformin 2/500-mg tablets versus separate tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Korean volunteers

• Published in: Clinical therapeutics 2010-07, Vol.32 (7), p.1408-1418
• Main Authors: Gu, Namyi, MD, Kim, Bo-Hyung, MD, Rhim, HyouYoung, MD, Chung, Jae-Yong, MD, PhD, Kim, Jung-Ryul, MD, PhD, Shin, Hyun-Suk, MS, Yoon, Seo-Hyun, PhD, Cho, Joo-Youn, PhD, Shin, Sang-Goo, MD, PhD, Jang, In-Jin, MD, PhD, Yu, Kyung-Sang, MD, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antidiabetics; Area Under Curve; Asian Continental Ancestry Group; Bioavailability; Biological and medical sciences; Chromatography, Liquid - methods; combination; Cross-Over Studies; Diabetes; Drug Combinations; Drug dosages; Drug Therapy, Combination; Female; glimepiride; healthy subjects; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Internal Medicine; Korea; Male; Medical Education; Medical sciences; Medicine; metformin; Metformin - administration & dosage; Metformin - adverse effects; Metformin - pharmacokinetics; Patient compliance; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Sulfonylurea Compounds - administration & dosage; Sulfonylurea Compounds - adverse effects; Sulfonylurea Compounds - pharmacokinetics; Tablets; Tandem Mass Spectrometry - methods; Therapeutic Equivalency; University colleges; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.07.012

Abstract Objective: This study compared the bioavailability and tolerability of a fixed-dose combination (FDC) tablet of glimepiride/metformin 2/500 mg and glimepiride 2-mg + metformin 500-mg tablets administered separately in healthy Korean subjects. Methods: In this single-dose, open-label, 2-period crossover study, healthy Korean volunteers were randomly assigned to receive, in 1 of 2 randomized sequences, an FDC tablet of glimepiride/metformin 2/500 mg (test) and glimepiride 2-mg + metformin 500-mg tablets administered separately (reference), with a 1-week washout period between treatments. Plasma concentrations of glimepiride and metformin were measured using LC/MS-MS. Pharmacokinetic parameters were analyzed using noncompartmental methods. Bioequivalence was concluded if the 90% CIs of the geometric mean test/reference ratios (GMRs) of the logarithm-transformed Cmax , AUC from 0 to 30 hours (AUC0–30 ), and AUC0−∞ values were within the predetermined regulatory range of 80% to 125%. Tolerability was assessed using physical examination and laboratory analysis. Results: A total of 32 subjects were enrolled (16 men [mean (SD) age, 21.8 (2.7) years (range, 18–26 years); weight, 68.9 (8.3) kg (range, 55.5–85.0 kg)]; 16 women [age, 23.5 (4.5) years (range, 20–38 years); weight, 51.7 (3.5) kg (range, 46.8–58.0 kg)]). The GMRs (90% CI) of glimepiride Cmax , AUC0–30 , and AUC0−∞ were 1.01 (0.91–1.11), 0.98 (0.92–1.03), and 0.97 (0.93–1.04), respectively. For metformin, these values were 0.96 (0.87–1.06), 0.96 (0.90–1.03), and 0.96 (0.90–1.03). A total of 49 adverse events (AEs) were reported in 10 subjects (31.3%) with the FDC and in 13 subjects (40.6%) with the separate tablets. The most commonly reported AEs with the test and reference treatments were dizziness (6 [19%] and 7 [22%]) and sweating (4 [13%] and 7 [22%]), respectively. The severity of all of the AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. Conclusions: In this study in healthy Korean subjects, the requirements for bioequivalence of the glimepiride/metformin 2/500-mg FDC and coadministration of separate tablets of each drug were met. Both formulations were generally well tolerated.