Effects of renal impairment on the pharmacokinetics, safety, and tolerability of pudexacianinium (ASP5354) after IV administration: a mechanistic exploration

To elucidate mechanisms of renal excretion of pudexacianinium (ASP5354) and evaluate renal impairment effects on pharmacokinetics, safety, and tolerability of pudexacianinium. Transcellular transport and transporter-mediated uptake of pudexacianinium were investigated in cells expressing human renal drug transporters P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, and MATE2-K. A Phase 1, open-label, parallel-group study (N = 28) was conducted in 6 participants each with mild, moderate, and severe renal impairment; 10 with normal renal function. Participants received a single intravenous dose of pudexacianinium 3 mg. Plasma and urine were collected post-dosing for pharmacokinetics. In vitro, pudexacianinium was not a substrate of the drug transporters tested. In humans, mean maximum concentration of pudexacianinium in plasma was comparable across study groups regardless of renal impairment. Systemic exposure was highest with severe renal impairment and decreased in parallel with renal impairment severity. Geometric least-squares mean ratios for area under the plasma concentration–time curve from time 0 to time infinity were 1.53, 2.30, and 3.69, respectively, for mild, moderate, and severe renal impairment, versus matched participants with normal renal function. During the 48-h collection, 64% of pudexacianinium was recovered unchanged in urine in the severe renal impairment group versus ≥ 90% recovered in other groups. Mean renal clearance was comparable with estimated glomerular filtration rate of unbound drug. Pudexacianinium was well tolerated, with an acceptable safety profile. Pudexacianinium elimination occurs primarily through glomerular filtration. Renal impairment significantly affected pudexacianinium pharmacokinetics. Single intravenous doses of pudexacianinium were generally tolerable in all participants, regardless of renal impairment. Trial registration. ClinicalTrials.gov identifier: NCT05495581, registered August 9, 2022.