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Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers

  • Clinical Trial
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Abstract

Purpose

SPT-07A is an intravenous injection of (+)-2-borneol being developed for the treatment of acute ischemic stroke. This study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of SPT-07A after sequentially administered single and multiple infusions of SPT-07A at 10 mg, 20 mg, or 40 mg.

Methods

This phase I, double-blind, randomized, placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to receive SPT-07A or matching placebo during the two study occasions, that is, an initial single-dose occasion followed by a 7-day multiple-dose occasion with a dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding effects on the central nervous system (CNS) were performed pre-dose and several times post-dose. Safety and tolerability were evaluated throughout the study for each cohort.

Results

Following single intravenous (i.v.) administration of 10 mg to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of infusion. Thereafter, the plasma concentration declined in a multiphase exponential manner with an average terminal elimination half-life of 3.85 to 8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with minimal accumulations. No significant difference of change-from-baseline was observed in the pharmacodynamic measurements between each of the three SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs were mild or moderate in severity and self-limited. SPT-07A was mainly excreted in human urine in glucuronic acid conjugate forms. The total urine recovery rate approximated 84.69% of the administered dose.

Conclusions

SPT-07A was safe and well tolerated after single and multiple intravenous administrations of SPT-07A in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in human. Based on plasma exposure, the doses of 10–40 mg twice daily resulted in exposure levels comparable with those obtained at doses demonstrating potential efficacy on AIS animal models and were thus recommended as therapeutic exploratory doses in the phase II clinical trial.

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Acknowledgments

The authors would like to thank Suzhou Pharmavan Co., Ltd. for sponsoring this study. We also would like to express our gratitude to all the volunteers who participated in the study for your contribution to medicine and to science.

Funding

This study was supported by National Grant for New Drug Development 2017ZX09304018 and Chinese National Natural Fund Grant 81671369.

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Authors and Affiliations

  1. Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China

    Weicong Wang, Yan Wang, Weiwei Zhao, Jingbo Zhong, Yongjun Wang & Xia Chen

  2. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China

    Yongjun Wang

  3. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, People’s Republic of China

    Yongjun Wang

Authors
  1. Weicong Wang
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  2. Yan Wang
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  3. Weiwei Zhao
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  5. Yongjun Wang
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  6. Xia Chen
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Contributions

Xia Chen and Yongjun Wang designed the research. Xia Chen and Weicong Wang wrote the clinical trial protocol. Xia Chen, Weicong Wang, Yan Wang, Weiwei Zhao, and Jingbo Zhong performed the research. Weicong Wang wrote the manuscript. All authors contributed towards critically revising the manuscript for important intellectual content, approve the final manuscript, and agree to be accountable for all aspects of the work and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Xia Chen.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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The authors declare that they have no conflict of interest.

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The authors confirm that the Principal Investigator for this paper is Xia Chen and Yongjun Wang and that they had direct clinical responsibility for patients.

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Wang, W., Wang, Y., Zhao, W. et al. Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers. Eur J Clin Pharmacol 76, 785–793 (2020). https://doi.org/10.1007/s00228-020-02851-x

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