Safety and pharmacokinetic interaction between fotagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin in healthy subjects

ABSTRACT

Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors have significant clinical efficacy for type 2 diabetes mellitus (T2DM). The combination of fotagliptin (FOT) with metformin (MET) is a promising therapeutic approach in MET-resistant patients. The aim of the present study was to evaluate the pharmacokinetic (PK) interaction between FOT and MET in healthy subjects after multiple-dose administration.

Methods

Eighteen participants received a randomized open-label, three period treatment that included MET 1000 mg alone, co-administration of FOT 24 mg and MET, followed by FOT 24 mg alone. Serial blood samples were collected for PK analysis, which included geometric mean ratios (GMRs) with 90% confidence intervals (CIs), area under the concentration–time curve (AUC), and maximum plasma concentration (C_max).

Results

Analysis results showed that for FOT alone or combination therapy, the 90% CIs of the GMR for AUC_0-24,ss and C_max,ss were 102.08% (98.9%, 105.36%) and 110.65% (102.19%, 119.82%), respectively. For MET, they were 113.41% (100.32%, 128.22%) and 97.11% (83.80%, 112.55%) for AUC_0-12,ss and C_max,ss, respectively. FOT or MET monotherapy and the combination therapy with both drugs were well tolerated.

Conclusions

No PK drug-drug interactions were found in the combination therapy with FOT and MET. Therefore, FOT can be co-administered with MET without dose adjustment.

Trial registration

The trial is registered at http://www.chinadrugtrials.org.cn/(Registration No. CTR20190221).

KEYWORDS:

• Fotagliptin benzoate
• pharmacokinetics
• drug-drug interaction
• safety
• type 2 diabetes mellitus

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

The authors are solely responsible for the design and conduct of this study. MW and YHD performed a review of the topic, and wrote and revised the manuscript. HZ took part in the analysis of the PK and PD data. CYL,WBZ, HGS, YL, and MW helped draft the manuscript. YL and HGS took part in the analysis and interpretation of data, prepared all figures and tables. YHD contributed to the study by writing the manuscript and providing critical revision. All the authors approved the final version of the manuscript.

Additional information

Funding

This paper was funded by the National Major Scientific and Technological Special Project for Significant New Drug Development during the Thirteenth Five-Year Plan Period of China (Project: 2017ZX09304004, 2017ZX09101001-002-004) and the National Scientific Foundation of China (Project: 81602897)