Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study

ABSTRACT

Background: The pharmacokinetics (PK), safety, and tolerability profiles of ZSP1601, a first-in-class pan-phosphodiesterase (PDE) inhibitor, were evaluated in healthy Chinese volunteers.

Research design and methods: This Phase 1a study consisted of a double-blinded, randomized, placebo-controlled single ascending dose (SAD) (25 to 350 mg), multiple ascending doses (MAD) (50 or 100 mg QD), and a two-period crossover food effect study (100 mg).

Results: ZSP1601 was quickly absorbed, with maximum plasma concentrations (C_max) reached at 1.25 to 2.50 h (median T_max). The exposures exhibited dose-proportional increases, while the mean half-life (t1/2) ranged from 6.34–8.64 h. Steady-state was reached within seven days in the MAD study. The mean steady trough concentrations were 423 and 588 ng/mL, respectively. ZSP1601 accumulation was low, with ratios ≤ 1.5. The bioavailability of ZSP1601 was equivalent under fasted and fed states. All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study.

Conclusions: The safety and PK profiles of ZSP1601 support further efficacy evaluation in nonalcoholic steatohepatitis patients.

Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).

KEYWORDS:

• Food effect
• pharmacokinetics
• safety
• tolerability
• ZSP1601

Note

The abstract has been previously posted at AASLD The Liver Meeting 2019 hosted in Boston (11/8/2019-11/12/2019)

Acknowledgments

We would like to thank all the healthy volunteers for their participation. This study was funded by Guangdong Raynovent Biotech Co., Ltd. This work was also financially supported by the National Major Scientific and Technological Special Project for “Significant New Drug Development” during the 13th Five-Year Plan Period of China (Project: 2017ZX09304004, 2017ZX09101001-002-004, and 2018ZX09201002-002-001), and the National Natural Science Foundation of China (Project: 81602897). The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).

Author contributions

Conceptualization, Haijun Li. and Yanhua Ding; methodology,Yanhua Ding.,Hong Wang; validation, Junjie Lin, formal analysis, Xiaoxue Zhu, Cuiyun Li; investigation, Xiaoxue Zhu, Cuiyun Li, Min Wu, Yue Hu ; resources, Yun Peng; writing—original draft preparation, Cuiyun Li; writing—review and editing, Haijun Li and Yanghua Ding; supervision, Yanghua Ding. All authors have read and agreed to the published version of the manuscript. All authors agree to be accountable for all aspects of the work.

Declaration of interest

Haijun Li and Junjie Lin are the employees of Guangdong Raynovent Biotech Co., Ltd. Yun Peng is the employee of Guangdong Zhongsheng Pharmaceutical Co., Ltd. The authors have no other 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

Additional information

Funding

China National Major Scientific and Technological Special Project: [2017ZX09101001-002-004, 2017ZX09304004, 2018ZX09201002-002-001]; National Natural Science Foundation of China [81602897]