Pharmacokinetics, safety, and tolerability of HRS-8427, a novel anti-carbapenem-resistant cephalosporin, in healthy subjects

HRS-8427 is a novel parenteral siderophore cephalosporin that shows potent efficacy against various gram-negative bacteria, including carbapenem-resistant strains, <i>in vitro</i> and in preclinical models of infection. It underwent a single-dose ascending study (400-6,000 mg) and a multiple-dose ascending study (1,000-3,000 mg q8h) in healthy Chinese adults to evaluate pharmacokinetics (PK), safety, and tolerability. A total of 62 treatment-emergent adverse events (TEAEs) occurred in 29 subjects during the treatment period, resulting in a TEAE incidence of 36.7% (29/79). There were no serious adverse events (AEs) observed in either study. Three subjects (one in the 2,000 mg single-dose group and two in the 3,000 mg multi-dose group) withdrew from the trial due to AEs. Approximately dose-proportional increases in the maximum plasma concentration (<i>C</i>_max) and the area under the concentration-time curve (AUC) were observed across the single-dose range of 400-6,000 mg, although the drug exposure increased slightly less than the dose. The mean plasma half-life of HRS-8427 was 3.89 to 4.28 h. HRS-8427 was primarily excreted unchanged in the urine (62.13% to 71.12% of the dose). There was minimal systemic accumulation of <i>C</i>_max and AUC by dosing q8h, and the PK of HRS-8427 did not change with multiple dosing. This study indicates that both single and multiple intravenous doses of HRS-8427, up to 6,000 mg and 2,000 mg, respectively, are well tolerated in healthy subjects and show generally linear pharmacokinetics at doses up to 6,000 mg.This study is registered with the Chinese Clinical Trial registry as ChiCTR2200062570, and ClinicalTrials.gov as NCT07070375, NCT06144060, NCT06569056, NCT06841731, NCT07049562, NCT07049107, and NCT07073157.