A first-in-human study of Brozopentyl Sodium, following single and multiple ascending intravenous infusion in Chinese healthy volunteers.

BACKGROUND:Brozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation. PURPOSE:This study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers. METHODS:The study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2-6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted. RESULTS:In the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated. CONCLUSION:BZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.