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Pharmacokinetics, Safety Profile, and Tolerability of Tetramethylpyrazine Nitrone Tablets After Single and Multiple Ascending Doses in Healthy Chinese Volunteers

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Abstract

Background and Objectives

Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative armed with a strong free radical scavenging nitrone moiety. This study aims to evaluate the pharmacokinetics, safety profile, and tolerability of TBN tablets after a single ascending dose (SAD) and multiple ascending doses (MAD) in healthy Chinese volunteers.

Methods

This phase I, single-center, open-label study was conducted in China. The SAD portion consisted of four cohorts with dose levels of 400–1800 mg. The MAD portion included three cohorts in which subjects received doses of 600–1800 mg twice daily for 7 days (13 consecutive doses). The third portion was a randomized, two-period, crossover design to assess the influence of food with a single dose of TBN tablets (1200 mg). The safety profile was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, physical examinations, and laboratory test results.

Results

Fifty-two healthy subjects aged 18 to 45 years with a body mass index between 19.0 and 26.0 kg/m2 were enrolled. After a single dose of TBN, the median time to maximum plasma concentration (Tmax) was 2.48–3.24 h and the mean half-life (t1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median Tmax was 2.48 to 3.48 h. In the 400–1800 mg dose range, there was a tendency for less than proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC0–t), and the area under the concentration-time curve from 0 to infinity (AUC0–inf) in both single- and multiple-dose periods. A significantly higher TBN exposure was observed in females than males in both a single and multiple doses of the 600 mg and 1200 mg groups, with a geometric mean female-to-male ratio of 138.69–203.18%. Food decreased the Cmax and AUC0–t of TBN to 45.19% and 59.73%, respectively. Each dose group reached a steady state after 4 days. No drug accumulation was observed. Two subjects had drug-related AEs. A decreased neutrophil count and drug eruption in the SAD portion (1200 mg group) and an increased alanine aminotransferase level in the food effect group were found. All AEs were mild and tolerable (CTCAE grade 1) and resolved without any medical intervention.

Conclusion

TBN tablets had a good safety profile and were well tolerated in healthy Chinese volunteers. Steady-state concentrations were reached after 4 consecutive days of oral administration. The results of this phase I study will provide guidance for the design of future TBN clinical studies.

Chinese Clinical Trial Registry

ChiCTR1900022092.

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Acknowledgements

Many thanks to Ms. Linda Wang of Guangzhou Magpie Pharmaceuticals Co., Ltd., for editing the manuscript.

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Authors and Affiliations

  1. Haikou People’s Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, Hainan, China

    Gangzhi Zhu, Liu Wang, Shaojin Zhong, Shengnan Han, Hui Peng, Mei Tong & Xiaoai He

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  1. Gangzhi Zhu
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Corresponding author

Correspondence to Xiaoai He.

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Author contributions

Study concept and design: GZ, LW, and XH. Data acquisition: SZ, and SH. Data analysis and interpretation: SZ, SH, HP, and MT. GZ was primarily responsible for drafting the manuscript and all authors reviewed, edited, and approved the manuscript before submission.

Funding

This work was partially supported by the Scientific Projects of Guangdong Province (2020A050515008); the Technology Innovation Project of Foshan (2017IT100153); and Guangzhou Magpie Pharmaceuticals Co., Ltd.

Conflict of interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Ethics approval

The clinical study met all local legal and regulatory requirements. The studies were conducted under contract with Guangzhou Magpie Pharmaceutical Co., Ltd., by the following research organizations, with approval from their ethical review committees: Haikou People's Hospital (approval number: 2019-(ethical review)-002, approval date: April 18, 2019). All procedures in these studies were performed in accordance with the 1964 Helsinki Declaration (and its amendments).

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Consent to participate

Informed consent was obtained from all individual participants prior to the initiation of any study-related procedure.

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Supplementary file1 (PDF 211 KB)

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Zhu, G., Wang, L., Zhong, S. et al. Pharmacokinetics, Safety Profile, and Tolerability of Tetramethylpyrazine Nitrone Tablets After Single and Multiple Ascending Doses in Healthy Chinese Volunteers. Eur J Drug Metab Pharmacokinet 49, 207–217 (2024). https://doi.org/10.1007/s13318-024-00877-5

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