Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes^*

ABSTRACT

Objective: Metformin is widely used for treating patients with type 2 diabetes, often as first-line therapy; however, many patients with type 2 diabetes are unable to maintain adequate glycemic control with metformin alone. Vildagliptin, an orally active, potent and selective dipeptidyl peptidase IV (DPP-4) inhibitor, may represent an appropriate antihyperglycemic agent for combination with metformin to improve glycemic control in such patients. This study assessed the effects of coadministration of vildagliptin and metformin on the steady-state pharmacokinetics of each drug.

Research design and methods: In this open-label, single-center, randomized, three-period, three-treatment crossover study, 17 patients with type 2 diabetes received vildagliptin 100 mg once daily; metformin 1000 mg once daily; or vildagliptin 100 mg once daily plus metformin 1000 mg once daily. Blood samples for pharmacokinetic sampling were taken frequently on the final day (Day 5) of each treatment period. Lack of pharmacokinetic interaction was defined as the ratio of geometric mean (GMR) and 90% confidence interval (CI) for combination:monotherapy being within the range 0.80–1.25.

Results: Coadministration with metformin had no effect on vildagliptin AUC_0–24 (GMR, 0.94; 90% CI 0.90, 0.99) although there was an 18% decrease in vildagliptin C_max (GMR 0.82; 90% CI 0.73, 0.91). Coadministration with vildagliptin had no effect on metformin C_max (GMR 1.04; 90% CI 0.94, 1.16). but caused a 15% increase in AUC_0–24 (GMR 1.15; 90% CI 1.06, 1.25). Both monotherapies and combination therapy were well tolerated. Seven patients reported a total of 10 adverse events; none was serious.

Conclusions: Coadministration of vildagliptin and metformin had a small effect on the pharmacokinetics of each drug in patients with type 2 diabetes; however, this is not likely to be clinically relevant. This small, open-label trial suggests that vildagliptin could be coadministered with metformin without any dose adjustment for either agent.

Key words: :

• DPP-4 inhibitor
• Drug-drug interactions
• Metformin
• Type 2 diabetes
• Vildagliptin

Acknowledgements

Declaration of interest: This work was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. All authors except for J.H. are employees of Novartis Pharmaceuticals Corporation and are thus eligible for Novartis stock and stock options. J.H. has no conflicts of interest to declare with regards to the contents of this article.

The authors thank Dr Joelle Campestrini and Dr Henri Humbert, Novartis Pharma S.A.S., Rueil-Malmaison, France, for carrying out the pharmacokinetic measurements.

The authors participated in the study design and the writing of the study protocol, approved the final protocol, participated in the collection, analysis, and interpretation of data, in the writing of the manuscript and approved the final manuscript. The authors take full responsibility for the contents of the article. Editorial assistance in the preparation of this manuscript was provided by Dr Ann Taylor of Oxford PharmaGenesis™ Ltd. Support for this assistance was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Notes

* These results have been presented as a poster at the American Society for Clinical Pharmacology and Therapeutics annual meeting, Baltimore, USA; 8–11 March 2006