Effects of renal impairment and hemodialysis on the pharmacokinetics and safety of HRS-8427, a siderophore cephalosporin for Gram‐negative bacterial infections

HRS-8427, a development-stage siderophore cephalosporin antibiotic, is being investigated for the treatment of aerobic Gram-negative bacterial infections, encompassing urinary tract infections and pulmonary infections. Participants with these indications frequently exhibit concomitant renal impairment (RI). Data from clinical studies suggest that ~60% to ~70% of unchanged HRS-8427 is excreted renally. A phase 1, multicenter, open-label study evaluated the effects of RI on the pharmacokinetics and safety of HRS-8427. In sub-study 1, 21 participants with mild to severe RI who were not on dialysis and six participants with normal renal function received single doses of 1,000 mg HRS-8427. In sub-study 2, six participants with end-stage renal disease (ESRD) requiring hemodialysis (HD) received single doses of the 1,000 mg HRS-8427 under dialysis and non-dialysis conditions, respectively. Plasma HRS-8427 area under the concentration-time curve from zero to infinity (AUC_0-∞) was ~1.2-fold, ~1.4-fold, 2.0-fold, and ~2.0-fold higher, respectively, in participants with mild, moderate, severe RI, and ESRD (without HD) relative to healthy controls. In dialysis-dependent subjects, the systemic exposure of HRS-8427 when dosed before HD was equivalent to 50.6% of that when dosed after HD. Adverse events (AEs) were mostly mild, and RI did not appear to be associated with an increased risk of AEs.CLINICAL TRIALSThis study is registered with http://www.chinadrugtrials.org.cn/ as CTR20230658.