Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone, a thiazolidinedione antihyperglycemic agent, in healthy subjects

Abstract

Objective:

Lobeglitazone as a thiazolidinedione antihyperglycemic agent activates peroxisome proliferator-activated receptor (PPAR) γ and may be suitable as monotherapy or in combination with other antihyperglycemic agents. The primary objective of this study was to investigate potential pharmacokinetic interactions between lobeglitazone and metformin in healthy Korean subjects.

Methods:

A randomized, open-label, multiple-dose, three-treatment, three-period, three-sequence, crossover study was conducted in 24 healthy Korean male volunteers. Serial blood samples were collected after lobeglitazone (0.5 mg/day) and metformin (1000 mg/day) were administered alone or concomitantly for 5 days in each period, and drug concentrations were determined by liquid chromatography–tandem mass spectrometry.

Clinical trail registration number:

ClinicalTrials.gov identifier: NCT01005160.

Results:

The steady-state maximum plasma concentrations (C_max, ss; mean ± standard deviation) of lobeglitazone and metformin alone were 29.38 ± 5.25 ng/mL and 1661.84 ± 471.88 ng/mL, respectively; the C_max, ss during co-administration were 27.15 ± 5.75 ng/mL and 1779.92 ± 405.20 ng/mL, respectively. The steady-state areas under the concentration–time curves during the dose interval (AUC_τ, ss; mean ± standard deviation) of sole administration of lobeglitazone and metformin were 277.53 ± 65.25 ng*h/mL and 9650.27 ± 2089.81 ng*h/mL, respectively. When lobeglitazone and metformin were administered concomitantly, the AUC_τ, ss were 257.29 ± 60.61 ng*h/mL and 10600.58 ± 1960.40 ng*h/mL, respectively. The geometric mean ratios (90% confidence interval) of co-medication to lobeglitazone alone were 0.92 (0.87–0.97; C_max, ss) and 0.93 (0.87–0.99; AUC_τ, ss), and those for co-medication to metformin monotherapy were 1.09 (0.99–1.19; C_max, ss) and 1.11 (1.04–1.19; AUC_τ, ss). Both monotherapies and combination therapy were well tolerated; 52 self-resolving, non-serious adverse events were reported from 17 subjects.

Conclusion:

Lobeglitazone did not significantly affect the pharmacokinetics of metformin or vice versa when both drugs were co-administered. Lobeglitazone can be co-administered with metformin without dose adjustment for either agent. Therefore further patient studies are needed to corroborate these results.

Keywords::

• Drug interactions
• Healthy subjects
• Lobeglitazone
• Metformin
• Pharmacokinetics

Transparency

Declaration of funding

This study was sponsored by the Chong Kun Dang Pharmaceutical Corp., Seoul, Korea. The sponsor did not play a major role in study design and data analysis.

Declaration of financial/other relationships

D.S., T.-E.K., S.H.Y., J.-Y.C., S.-G.S., I.-J.J., and K.-S.Y. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

This work was supported by the Medicine and Bio Project for ‘Development of New Medicine and Medical Material’ of the Chungcheong Leading Industry Office of the Korean Ministry of Knowledge Economy, which is a government organization (70007613, ‘Clinical development of lobeglitazone, a thiazolidinedione insulin sensitizing agent for diabetes mellitus’). D.S. was supported by a training program grant from the Korea Healthcare Technology Research and Development Project, Ministry for Health, Welfare, and Family Affairs of Republic of Korea (A070001). The authors thank Ms. Jungmi Baik and Ms. Sangsuk Yoon (Clinical Trials Center at Seoul National University Hospital) for their assistance with the conduct of the clinical trial.

Previous presentation: material contained in this paper has been previously published as an abstract in Clin Pharmacol Ther 2010;89:S90 and presented as a poster at the annual meeting of American Society for Clinical Pharmacology and Therapeutics, 2–5 March 2011, Dallas, TX, USA.