Intrapulmonary penetration and pharmacokinetics of siderophore cephalosporin HRS-8427 injection in Chinese healthy subjects.

HRS-8427, a novel siderophore cephalosporin antibiotic, is under development for treating Gram-negative infections. This study evaluated the intrapulmonary penetration and pharmacokinetic (PK) profile of HRS-8427 injection following single and multiple dose administrations in healthy Chinese subjects. A single-center, randomized, open-label Phase 1 trial enrolled 38 subjects, with 35 completing the study. In the single-dose group, subjects received a 1,500 mg intravenous infusion of HRS-8427 over 2 h. In the multiple-dose group, subjects were administered 2,000 mg of HRS-8427 intravenously every 8 h for four consecutive doses, each infused over 2 h. Bronchoalveolar lavage (BAL) was conducted to collect epithelial lining fluid (ELF) and alveolar macrophage (AM) specimens. PK analysis demonstrated a maximum plasma concentration (Cmax) of 176 µg/mL and an area under the time-concentration curve from time zero to time infinity (AUC0-∞) of 942 h·μg/mL following the single 1,500 mg dose. After multiple 2,000 mg dosing, the Cmax increased to 262 µg/mlL with a corresponding AUC0-∞ of 1,640 h·μg/mL. The ELF-to-plasma concentration ratio (CELF/Cplasma) exhibited a time-dependent increase, reaching 12.2% at 8 h post-final dose. Intracellular accumulation in AM remained minimal (<1%). Multiple-dose administration resulted in higher ELF exposure than single dosing. Safety assessments indicated an overall favorable tolerability profile, with most adverse events being mild in severity. Based on PK and microbiological data, a 2,000 mg regimen achieved concentrations exceeding the MIC₉₀ values of major Gram-negative pathogens, supporting further clinical development of HRS-8427 for respiratory and other Gram-negative bacterial infections.CLINICAL TRIALSThis study is registered with Chinese Clinical Trial Registry Platform as ChiCTR2300072350.