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

Namyi Gu; Bo Hyung Kim; Hyou Young Rhim; Jae Yong Chung; Jung Ryul Kim; Hyun Suk Shin; Seo Hyun Yoon; Joo Youn Cho; Sang Goo Shin; In Jin Jang; Kyung Sang Yu

doi:10.1016/j.clinthera.2010.07.012

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

Namyi Gu
, Bo Hyung Kim
, Hyou Young Rhim
, Jae Yong Chung
, Jung Ryul Kim
, Hyun Suk Shin
, Seo Hyun Yoon
, Joo Youn Cho
, Sang Goo Shin
, In Jin Jang
, Kyung Sang Yu

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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 C _max, AUC from 0 to 30 hours (AUC _0-30), and AUC _0- 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- 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.

Original language	English
Pages (from-to)	1408-1418
Number of pages	11
Journal	Clinical Therapeutics
Volume	32
Issue number	7
DOIs	https://doi.org/10.1016/j.clinthera.2010.07.012
Publication status	Published - Jul 2010

Bibliographical note

Funding Information:
All of the authors provided substantial contributions to the development and conduct of the study. Dr. Gu conducted statistical analyses, literature searches, and manuscript writing. Dr. Gu’s contributions were supported by a training-program grant from the Korea National Enterprise for Clinical Trials. Drs. B.-H. Kim and Yu participated in the study design, data analyses, and writing and review of the manuscript. Dr. Rhim participated in the study design. Drs. Chung and J.-R. Kim were subinvestigators in the study and contributed to data analyses. H.-S. Shin and Drs. Yoon and Cho conducted the bioanalyses and reviewed the manuscript. Dr. Jang was the principal investigator. The sponsor was not involved in the design, conduct, or analysis of the study. The authors thank Dr. Woo Ick Jang, Handok Pharmaceutical Co., for review of the manuscript.

Keywords

Combination
Glimepiride
Healthy subjects
Metformin
Pharmacokinetics

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Gu, N., Kim, B. H., Rhim, H. Y., Chung, J. Y., Kim, J. R., Shin, H. S., Yoon, S. H., Cho, J. Y., Shin, S. G., Jang, I. J., & Yu, K. S. (2010). 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. Clinical Therapeutics, 32(7), 1408-1418. https://doi.org/10.1016/j.clinthera.2010.07.012

@article{ec8b5173b52240d69282a02f3910874b,

title = "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",

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 C max, AUC from 0 to 30 hours (AUC 0-30), and AUC 0- 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- 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.",

keywords = "Combination, Glimepiride, Healthy subjects, Metformin, Pharmacokinetics",

author = "Namyi Gu and Kim, \{Bo Hyung\} and Rhim, \{Hyou Young\} and Chung, \{Jae Yong\} and Kim, \{Jung Ryul\} and Shin, \{Hyun Suk\} and Yoon, \{Seo Hyun\} and Cho, \{Joo Youn\} and Shin, \{Sang Goo\} and Jang, \{In Jin\} and Yu, \{Kyung Sang\}",

note = "Funding Information: All of the authors provided substantial contributions to the development and conduct of the study. Dr. Gu conducted statistical analyses, literature searches, and manuscript writing. Dr. Gu{\textquoteright}s contributions were supported by a training-program grant from the Korea National Enterprise for Clinical Trials. Drs. B.-H. Kim and Yu participated in the study design, data analyses, and writing and review of the manuscript. Dr. Rhim participated in the study design. Drs. Chung and J.-R. Kim were subinvestigators in the study and contributed to data analyses. H.-S. Shin and Drs. Yoon and Cho conducted the bioanalyses and reviewed the manuscript. Dr. Jang was the principal investigator. The sponsor was not involved in the design, conduct, or analysis of the study. The authors thank Dr. Woo Ick Jang, Handok Pharmaceutical Co., for review of the manuscript.",

year = "2010",

month = jul,

doi = "10.1016/j.clinthera.2010.07.012",

language = "English",

volume = "32",

pages = "1408--1418",

journal = "Clinical Therapeutics",

issn = "0149-2918",

publisher = "Elsevier Inc.",

number = "7",

}

Gu, N, Kim, BH, Rhim, HY, Chung, JY, Kim, JR, Shin, HS, Yoon, SH, Cho, JY, Shin, SG, Jang, IJ & Yu, KS 2010, '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', Clinical Therapeutics, vol. 32, no. 7, pp. 1408-1418. https://doi.org/10.1016/j.clinthera.2010.07.012

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. / Gu, Namyi; Kim, Bo Hyung; Rhim, Hyou Young et al.
In: Clinical Therapeutics, Vol. 32, No. 7, 07.2010, p. 1408-1418.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Comparison of the bioavailability and tolerability of fixed-dose combination glimepiride/metformin 2/500-mg tablets versus separate tablets

T2 - A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Korean volunteers

AU - Gu, Namyi

AU - Kim, Bo Hyung

AU - Rhim, Hyou Young

AU - Chung, Jae Yong

AU - Kim, Jung Ryul

AU - Shin, Hyun Suk

AU - Yoon, Seo Hyun

AU - Cho, Joo Youn

AU - Shin, Sang Goo

AU - Jang, In Jin

AU - Yu, Kyung Sang

N1 - Funding Information: All of the authors provided substantial contributions to the development and conduct of the study. Dr. Gu conducted statistical analyses, literature searches, and manuscript writing. Dr. Gu’s contributions were supported by a training-program grant from the Korea National Enterprise for Clinical Trials. Drs. B.-H. Kim and Yu participated in the study design, data analyses, and writing and review of the manuscript. Dr. Rhim participated in the study design. Drs. Chung and J.-R. Kim were subinvestigators in the study and contributed to data analyses. H.-S. Shin and Drs. Yoon and Cho conducted the bioanalyses and reviewed the manuscript. Dr. Jang was the principal investigator. The sponsor was not involved in the design, conduct, or analysis of the study. The authors thank Dr. Woo Ick Jang, Handok Pharmaceutical Co., for review of the manuscript.

PY - 2010/7

Y1 - 2010/7

N2 - 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- 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- 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.

AB - 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- 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- 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.

KW - Combination

KW - Glimepiride

KW - Healthy subjects

KW - Metformin

KW - Pharmacokinetics

UR - https://www.scopus.com/pages/publications/77955240934

U2 - 10.1016/j.clinthera.2010.07.012

DO - 10.1016/j.clinthera.2010.07.012

M3 - Article

C2 - 20678687

AN - SCOPUS:77955240934

SN - 0149-2918

VL - 32

SP - 1408

EP - 1418

JO - Clinical Therapeutics

JF - Clinical Therapeutics

IS - 7

ER -

Gu N, Kim BH, Rhim HY, Chung JY, Kim JR, Shin HS et al. 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. Clinical Therapeutics. 2010 Jul;32(7):1408-1418. doi: 10.1016/j.clinthera.2010.07.012

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

Abstract

Bibliographical note

Keywords

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