Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers

Abstract

Objectives: To investigate the pharmacokinetic/pharmacodynamic interactions of the antidiabetic agents canagliflozin (a sodium-glucose cotransporter-2 inhibitor) and teneligliptin (a dipeptidyl peptidase-4 inhibitor) in Japanese healthy adult men.

Methods: Open-label, one-way crossover study used canagliflozin (200 mg/day p.o.) and teneligliptin (40mg/day p.o). A single dose of object drug (either canagliflozin or teneligliptin) was administered on day 1 followed by washout and continuous administration of precipitant drug (days 1 – 9). Both drugs were concomitantly administered on day 7.

Results: No changes in AUC_{0 – 72h} and C_max were observed for canagliflozin+teneligliptin versus monotherapy; geometric mean ratios for AUC_{0 – 72h} and C_max were 0.982 and 0.982 for the plasma concentration of canagliflozin and 0.983 and 0.976 for the plasma concentration of teneligliptin, respectively. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) increased with canagliflozin+teneligliptin versus teneligliptin alone. Mean AUC_{0.5 – 4h} increased post-meal, on combination therapy, from 9.6 to 12.5 pmol·h/l (active GLP-1) and from 21.5 to 32.3 pmol·h/l (total GLP-1). Adverse events developed in four subjects; all were mild and resolved but one subject withdrew due to generalized erythema.

Conclusions: GLP-1 levels increased with the canagliflozin+teneligliptin combination, and no PK interaction was observed. This combination may show favorable antidiabetic effects without increasing systemic exposure.

Keywords:

• canagliflozin
• DPP-4 inhibitor
• drug-drug interaction
• SGLT2 inhibitor
• teneligliptin

Acknowledgments

This study was funded by Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The authors thank Takashi Eto and Ippei Ikushima of Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital, respectively, for participating as investigators in the clinical trial. Data management and statistical analysis were undertaken by InCROM CRO Inc. Laboratory tests and measurements of active and total GLP-1 were done by the Mitsubishi Chemical Medience Corporation. The measurements of plasma concentration of canagliflozin and teneligliptin were carried out by JCL Bioassay Corporation and Sumika Chemical Analysis Service, Ltd., respectively. The Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital participated in this study as study centers.

Declaration of interest

S Kinoshita and K Kondo are employees of Mitsubishi Tanabe Pharma Corporation. This study was financially supported by Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The funding organization contributed to the study design, data collection and analysis. Manuscript writing assistance and editing services were provided by Sean Markwardt and Smitha Mathews. This work was presented, in part, as a poster at the 57th Annual Meeting of the Japan Diabetes Society, May 22, 2014, Osaka, Japan. Link: http://www2.convention.co.jp/jds57/english/index.html. The views expressed in the submitted article are those of the authors and not an official position of the institutions or funding organization.