Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients

Abstract

Objective:

Dutogliptin is a novel, orally available, potent, and selective DPP4 inhibitor that improves glycemic control in type 2 diabetic patients. The objective of this study was to evaluate the potential pharmacokinetic and pharmacodynamic interactions, as well as the tolerability, of dutogliptin and metformin alone and in combination in type 2 diabetic patients.

Methods:

This was a single-center, randomized, open-label, 3-way, crossover study in type 2 diabetic patients. All patients received three treatment regimens, each of 5 days duration in order to reach steady state: 400 mg once daily of dutogliptin (the anticipated clinical dose); 1000 mg metformin twice daily (maximum effective clinical dose); and concomitant administration of 400 mg dutogliptin once daily and 1000 mg metformin twice daily.

Results:

Co-administration of dutogliptin and metformin did not alter the pharmacokinetics of either agent. The geometric mean ratio, GMR (dutogliptin + metformin /dutogliptin) of the area under the plasma concentration-time curve (AUC_0–24h) at steady state was 0.91 (90% CI: 0.79–1.06; p = 0.29); the GMR of the maximum plasma concentrations (C_max) was 0.95 (90% CI: 0.76–1.19; p = 0.70); the time to maximum plasma concentrations (T_max) was essentially the same for dutogliptin with or without metformin. The GMR (dutogliptin + metformin/metformin) of AUC_0–12h at steady state was 0.99 (90% CI: 0.84–1.17; p = 0.93); the GMR of C_max was 0.91 (90% CI: 0.79–1.04; p = 0.18); T_max was comparable for metformin with or without dutogliptin. Metformin added to dutogliptin had no effect on plasma DPP4 inhibition. All three treatment regimens were well tolerated.

Conclusions:

In this small, multiple dose study, the steady state pharmacokinetics of either dutogliptin or metformin were not altered by co-administration of the two agents. Dutogliptin and metformin were well tolerated either alone or in combination and co-administered metformin did not alter the ex vivo DPP4 inhibition by dutogliptin. There is no need to consider pharmacokinetic and pharmacodynamic interactions when determining the dosage of either agent for co-administration. A phase 3 clinical trial is underway to provide more definitive data on the safety and efficacy of dutogliptin administered on a background of metformin treatment.

Key words::

• DPP4
• dutogliptin
• incretin
• metformin
• pharmacokinetics
• PHX1149

Transparency

Declaration of funding

This study was sponsored and funded by Phenomix Corporation.

Declaration of financial/other relationships

All authors, with the exception of S.S., have disclosed that they were employees of Phenomix Corporation at the time of the study. S.S. has disclosed that he was an employee of Diabetes and Glandular Diseases Clinic. Peer reviewers may receive honoraria from CMRO for their review work. The peer reviewers have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors thank Evelyn Gurganus for editorial support (funded by Phenomix Corporation), and the patients and staff who participated at the Diabetes and Glandular Diseases Clinic, San Antonio, TX.

Data from this study have been published, in part, as Poster 705-P, at the 70th Scientific Sessions of the American Diabetes Association, 25--29 June 2010.