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

Background and ObjectiveDifelikefalin, 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 [C-14]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD.MethodsTwelve adult males (n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [C-14]difelikefalin containing 100 & mu;Ci (total doses of 1.7-3.0 & mu;g/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing.ResultsThe 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 [C-14]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.ConclusionIn 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.RegistrationClinicalTrials.gov NCT03947970.