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

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 (T_max) was 2.48-3.24 h and the mean half-life (t_1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median T_max 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 (C_max), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC_0-t), and the area under the concentration-time curve from 0 to infinity (AUC_0-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 C_max and AUC_0-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.