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.
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 C(max), AUC from 0 to 30 hours (AUC(0-30)), and AUC(0-infinity) 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 C(max), AUC(0-30), and AUC(0-infinity) 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.
Gu
Namyi
N
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Korea.
Kim
Bo-Hyung
BH
Rhim
HyouYoung
H
Chung
Jae-Yong
JY
Kim
Jung-Ryul
JR
Shin
Hyun-Suk
HS
Yoon
Seo-Hyun
SH
Cho
Joo-Youn
JY
Shin
Sang-Goo
SG
Jang
In-Jin
IJ
Yu
Kyung-Sang
KS
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D002853:Chromatography, Liquid / Q000379:methods; D018592:Cross-Over Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007723:Korea; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry / Q000379:methods; D013810:Therapeutic Equivalency; D055815:Young Adult
D004338:Drug Combinations; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D013607:Tablets; C057619:glimepiride; D008687:Metformin