Clinical Drug Investigation

, Volume 38, Issue 6, pp 519–525 | Cite as

Safety and Pharmacokinetics of DS-8500a, a Novel GPR119 Agonist, After Multiple Oral Doses in Healthy Japanese Males

  • Manabu Kato
  • Hidetoshi Furuie
  • Emi Kamiyama
  • Kazuhito Shiosakai
  • Kazutaka Yoshihara
  • Takashi Taguchi
Original Research Article


Background and objectives

G protein-coupled receptor 119 (GPR119) agonists reduce plasma glucose by promoting insulin secretion in a glucose-dependent manner. We evaluated the safety and pharmacokinetics of multiple oral doses of DS-8500a, a GPR119 agonist, under fed conditions in healthy adult Japanese male subjects.


In this Phase 1, randomized, placebo-controlled, double-blind, multiple oral dose study, participants were aged ≥ 20 and ≤ 45 years with a body mass index ≥ 18.5 and < 25.0 kg/m2. DS-8500a 50 and 100 mg or placebo were administered orally, once daily, 30 min after breakfast for 7 days. The primary endpoints were pharmacokinetics and safety.


Twenty-four subjects were included (6, 9, and 9 in the placebo, 50-, and 100-mg groups, respectively). On Day 7, the mean maximum plasma concentration (Cmax) was 812 ng/mL in the 50-mg group and 1310 ng/mL in the 100-mg group. The mean area under the plasma concentration–time curve during dosing interval (AUCtau) was 7910 and 13,200 ng·h/mL in the two treatment groups, respectively. The observed accumulation ratio was 1.25 in the 50-mg group and 1.32 in the 100-mg group. All adverse events were mild and judged unrelated to the study drug.


DS-8500a plasma concentrations reached steady state from Day 3, and Cmax and AUCtau increased in a less than dose-proportional manner. After repeated doses of DS-8500a at 100 mg, the DS-8500a trough concentration was expected to reach a pharmacologically active dose. DS-8500a was well tolerated up to 100 mg after a 7-day administration.

Study registry identification

JAPIC ID: JapicCTI-173550 (registered retrospectively on 30 March 2017).



The authors would like to thank Rita Moreira da Silva, Helen Roberton, Emma Donadieu, and Mary Richardson of Edanz Medical Writing for providing medical writing services.

Compliance with Ethical Standards


This study was funded by Daiichi Sankyo Co., Ltd.

Conflicts of interest

MK, EK, KS, KY, and TT are employees of Daiichi Sankyo Co., Ltd. HF received research funding for this study from Daiichi Sankyo Co., Ltd.

Ethics approval

All procedures performed in this study were in accordance with the institutional and national ethical standards and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Kashima S, Inoue K, Matsumoto M, Akimoto K. Prevalence and characteristics of non-obese diabetes in Japanese men and women: the Yuport Medical Checkup Center Study. J Diabetes. 2015;7:523–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Goto A, Noda M, Inoue M, Goto M, Charvat H. Increasing number of people with diabetes in Japan: is this trend real? Intern Med. 2016;55:1827–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Ministry of Health, Labour and Welfare. The National Health and Nutrition Survey in Japan, 2012. Accessed 5 July 2017 (in Japanese).
  4. 4.
    National Institute for Health and Care Excellence (NICE). NICE Guideline NG28: algorithm for blood glucose lowering therapy in adults with type 2 diabetes. 2015. Accessed 5 July 2017.
  5. 5.
    Tan X, Hu J. Combination therapy for type 2 diabetes: dapagliflozin plus metformin. Expert Opin Pharmacother. 2016;17:117–26.CrossRefPubMedGoogle Scholar
  6. 6.
    Cefalu WT. American Diabetes Association: standards of medical care in diabetes—2016. J Clin Appl Res Educ. 2016;39:1–111.Google Scholar
  7. 7.
    Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602–13.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Shin MS, Yu JH, Jung CH, Hwang JY, Lee WJ, Kim MS, et al. The duration of sulfonylurea treatment is associated with beta-cell dysfunction in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2012;14:1033–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Soga T, Ohishi T, Matsui T, Saito T, Matsumoto M, Takasaki J, et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 2005;326:744–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, et al. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology. 2008;149:2038–47.CrossRefPubMedGoogle Scholar
  11. 11.
    Chu ZL, Jones RM, He H, Carroll C, Gutierrez V, Lucman A, et al. A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology. 2007;148:2601–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Yoshida S, Ohishi T, Matsui T, Tanaka H, Oshima H, Yonetoku Y, et al. The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic beta-cell function. Diabetes Obes Metab. 2011;13:34–41.CrossRefPubMedGoogle Scholar
  13. 13.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: food-effect bioavailability and fed bioequivalence studies. 2002. Accessed 7 Feb 2018.
  14. 14.
    Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 1974;27:365–75.CrossRefPubMedGoogle Scholar
  15. 15.
    Inagaki N, Chou HS, Tsukiyama S, Washio T, Shiosakai K, Nakatsuka Y, et al. Glucose-lowering effects and safety of DS-8500a, a G protein-coupled receptor 119 agonist, in Japanese patients with type 2 diabetes: results of a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase II study. BMJ Open Diabetes Res Care. 2017. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Manabu Kato
    • 1
  • Hidetoshi Furuie
    • 2
  • Emi Kamiyama
    • 1
  • Kazuhito Shiosakai
    • 3
  • Kazutaka Yoshihara
    • 1
  • Takashi Taguchi
    • 4
  1. 1.Clinical Pharmacology DepartmentDaiichi Sankyo Co., LtdTokyoJapan
  2. 2.Osaka Pharmacology Clinical Research HospitalOsakaJapan
  3. 3.Biostatistics & Data ManagementDaiichi Sankyo Co., LtdTokyoJapan
  4. 4.Clinical Development DepartmentDaiichi Sankyo Co., LtdTokyoJapan

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