Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis

Background and Objective Difelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [ 14 C]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD. Methods Twelve adult males ( n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [ 14 C]difelikefalin containing 100 µCi (total doses of 1.7–3.0 μg/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing. Results The median time to maximum concentration was similar for HD and healthy subjects, occurring at 5 min post-dose. The mean area under the concentration–time curve (AUC) was approximately 11-fold higher in HD versus healthy subjects; mean plasma half-life was 38.0 h and 2.6 h, respectively. In healthy subjects, 80.5% of the dose was recovered in urine, and 11.3% was recovered in feces. In subjects on HD, 58.8% of the dose was recovered in feces, and 19.5% was recovered in dialysate [for subjects on HD with residual kidney function ( n = 3), 11.2% was recovered in urine]. Based on plasma AUC last , parent [ 14 C]difelikefalin was the most abundant analyte in systemic circulation (> 99% of total exposure) for both cohorts. Metabolite profiles in urine and feces suggested minimal metabolism of the parent compound. Conclusion In subjects on HD, difelikefalin total exposure was higher and plasma half-life was longer compared with subjects with intact renal function. Metabolism was low in both healthy subjects and subjects on HD, with unchanged drug representing > 99% of systemic circulation; however, the route of excretion was primarily into urine versus feces in healthy subjects, and feces versus dialysate in subjects on HD. Registration ClinicalTrials.gov NCT03947970.