Tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534, a potent G protein-coupled receptor 40 (GPR40) agonist, at single- and multiple-ascending oral doses in healthy Chinese subjects

Abstract

1. SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study.

2. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded.

3. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a T_max of approximately 4 hours, and systemic exposure increased with dose. Accumulation was minimal (2- to 3-fold) and steady state was reached after seven days of dosing. For pharmacodynamics, no significant hypoglycaemic effects were seen in healthy adults.

4. Good pharmacokinetics and safety were demonstrated but no obvious effect was found.

Keywords:

• SHR0534
• GPR40 agonists
• pharmacokinetics
• pharmacodynamics
• safety and tolerability
• diabetes mellitus

Acknowledgments

Medical writing and editorial support were provided by Yuqing Zhao, MS, Feng Shao, PhD, Jie Wu, MD, PhD and Jingjing Wang, MS. Jiangsu Hengrui Medicine Co., Ltd. funded the study and provided the experimental tablets.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was sponsored by Jiangsu Hengrui Medicine Co., Ltd. and conducted in the First Affiliated Hospital with Nanjing Medical University. Yuqing Zhao, Lijun Xie, Ning Ou, Hongwen Zhang, Sufeng Zhou, Yun Liu, Juan Chen, Lu Wang, Libin Wang and Feng Shao are current employees of the First Affiliated Hospital with Nanjing Medical University. Jie Wu and Jingjing Wang are current employees of Jiangsu Hengrui Medicine Co., Ltd. Feng Shao is the PI for this paper and she has direct clinical responsibility for subjects.