Pharmacokinetics, Elimination and Dialyzability of HRS-9231 in Patients with Varying Degrees of Renal Impairment.

OBJECTIVES: This study aimed to characterize the pharmacokinetics (PK), elimination and dialysability of HRS‑9231, a novel macrocyclic gadolinium‑based contrast agent, in individuals with varying degrees of renal impairment, including those requiring hemodialysis. METHODS: In this open‑label, non‑randomized, Phase 1 study, 40 participants were stratified into five cohorts based on renal function: normal, mild, moderate, severe impairment, and end‑stage renal disease (ESRD). All received a single intravenous dose of HRS‑9231 (0.05 mmol/kg). Intensive PK sampling was performed over 96-120 h. End‑stage renal disease patients underwent hemodialysis sessions post‑dose, with concurrent plasma and dialysate collection. Long‑term gadolinium elimination and safety were monitored for up to 6 months. RESULTS: Systemic exposure to HRS‑9231 increased with renal impairment severity: geometric mean area under the plasma concentration versus time curve from zero to infinity (AUC0‑∞) was 35%, 104%, and 333% higher in mild, moderate, and severe impairment cohorts, respectively, versus normal function. Mean terminal half‑life prolonged from 1.7 h (normal) to 7.2 h (severe). Cumulative urinary excretion exceeded 85% across cohorts. In ESRD patients, hemodialysis efficiently removed HRS‑9231, with an 84% reduction in plasma concentration after the first session and concentrations falling below the limit of quantitation after three sessions. Gadolinium levels declined over time, returning to the unexposed reference range within 6 months. During the 6‑month follow‑up, no cases of nephrogenic systemic fibrosis (NSF) or related symptoms were observed. Given the low expected incidence of NSF with macrocyclic GBCAs and the limited sample size per cohort, this study was not statistically powered to definitively assess NSF risk. Nonetheless, the absence of NSF cases in this at‑risk population provides supportive evidence consistent with the established safety profile of macrocyclic GBCAs. CONCLUSIONS: HRS‑9231 exhibits a PK profile consistent with renal elimination. Its clearance decreases proportionally with renal impairment, and it is effectively cleared by hemodialysis. HRS‑9231 was generally well tolerated in this small cohort of patients with varying degrees of renal impairment, including those on hemodialysis. No new safety signals or NSF cases were identified. These findings, together with the PK data, support that dose adjustment is unlikely to be necessary for patients with any degree of renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06657560.