A Pharmacokinetic Drug Interaction Between Fimasartan and Linagliptin in Healthy Volunteers

Abstract

Objective

Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects.

Methods

The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs.

Results

Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (C_max,ss) and area under the concentration–time curve at steady state (AUC_τ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175–1.7396) and 1.1740 (1.0499–1.3126), respectively. The corresponding values for C_max,ss and AUC_τ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480–1.1336) and 0.9950 (0.9322–1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs.

Conclusion

Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects.

Clinical Trial Registry

http://clinicaltrials.gov, NCT03250052.

Keywords:

• fimasartan
• pharmacokinetics
• drug–drug interaction
• linagliptin
• safety

Acknowledgments

The authors are grateful to all study participants and volunteer subjects. This study was sponsored by Boryung Pharmaceutical Co. Ltd., Seoul, Korea, and was supported by the grants from Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI14C2750, HI15C0001) as well as the Industrial Core Technology Development Program (10051129, Development of the system for ADME assessment using radiolabeled compounds) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea).

Abbreviations

BP, blood pressure; t_max, time to peak concentration; t_1/2, terminal half-life; DPP-4, dipeptidyl-peptidase-4; CTC, clinical trial center; KNUH, Kyungpook National University Hospital; PK, pharmacokinetic; ECG, electrocardiogram; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; MRM, multiple reaction monitoring; IS, internal standard; CV, coefficient of variation; AUC_τ,ss, area under the concentration–time curve over a dosing interval τ at steady state; C_{max, ss}, maximum plasma concentration at steady-state; C_{trough, ss}, trough plasma concentration at steady state; T_{max, ss}, time from last dosing to maximum plasma concentration at steady-state; CL_ss/F, apparent clearance at steady state; TEAE, treatment emergent adverse event; GMR, geometric mean ratio; SD, standard deviation; CI, confidence interval; OAT1, organic anion transporter 1; OATP, organic anion-transporting polypeptide; Pgp, P-glycoprotein; OCT1, organic cation transporter 1.

Data Sharing Statement

We, the authors, intend to share individual de-identified participant data. However, there must be a limit on our data sharing, because this study was sponsored by a pharmaceutical company. Young-Ran Yoon should be contacted for the sharing of the data.

Disclosure

The authors report no conflicts of interest regarding the content of this article.