A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TPN171H, a Novel Phosphodiesterase Type 5 Inhibitor, in Healthy Subjects

Abstract

Purpose

TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.

Methods

The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.

Results

In Part I, AUC and C_max were proved to be linear within the 5–30 mg dose range. T_1/2 of TPN171H was 8.02–10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease C_max, prolong T_max, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and C_max indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination.

Conclusion

TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.

Keywords:

• TPN171H
• PDE5 inhibitor
• safety
• pharmacokinetics
• food effect
• healthy subjects

Acknowledgments

The authors sincerely thank the healthy subjects and staffs who participated in the clinical study. The authors acknowledge Clinical Service Center Co., Ltd for clinical monitoring of this study. The authors also acknowledge Meta Clinical Technology Co., Ltd for statistical analysis of this study.

Data Sharing Statement

The authors intend to share individual deidentified participant data, such as the individual PK and the safety data, in form of supplementary data. The data will be available from the corresponding authors Jingying Jia and Zhen Wang.

Ethical Statement

The study protocol was approved by the Ethics Committee of the Shanghai Xuhui Central Hospital and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. All subjects were required to provide written informed consent before any study-related procedure was performed.

Disclosure

Zhen Wang, Yu Wang, Jingshan Shen and Hualiang Jiang are the employees of Shanghai Institute of Materia Medica, the sponsor of this study. Guanghui Tian is the employee of Vigonvita Life Science Co., Ltd, the co-sponsor of this study.

Professor Jingshan Shen reports grants from National Health Commission of the People’s Republic of China, grants from Chinese Academy of Sciences, during the conduct of the study; holds the stock of Vigonvita Life Science Co., Ltd., outside the submitted work. In addition, Professor Jingshan Shen has a patent PCT/CN2009/001418 issued to Shanghai Institute of Materia Medica, Chinese Academy of Sciences, a patent PCT/CN2018/093965 issued to Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

Professor Hualiang Jiang reports grants from National Health Commission of the People’s Republic of China, grants from Chinese Academy of Sciences, during the conduct of the study. In addition, Professor Hualiang Jiang has a patent PCT/CN2018/093965 issued, a patent PCT/CN2009/001418 issued.

Professor Zhen Wang reports grants from National Health Commission of the People’s Republic of China, grants from Chinese Academy of Sciences, during the conduct of the study. In addition, Professor Zhen Wang has a patent PCT/CN2009/001418 issued, a patent PCT/CN2018/093965 issued.

The other authors report no conflicts of interest related to this work.

Additional information

Funding

This study was sponsored by Vigonvita Life Science Co., Ltd. The study was also supported by the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (No. 2018ZX09711002), and the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDA12040103).