Absorption, distribution, metabolism, and excretion of radiolabeled naldemedine in healthy subjects

Abstract

1. Naldemedine is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation.2. This phase 1 study investigated the absorption, distribution, metabolism and excretion of naldemedine, following a single oral 2-mg dose of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine to 12 healthy adult male subjects. Pharmacokinetic assessments were performed on blood, urine and fecal samples collected at defined intervals.3. Naldemedine was the major circulating component in plasma with a median Tmax of approximately 0.8–0.9 h and a geometric mean t1/2,z of approximately 11 h. Total systemic exposures, AUC, of metabolites nor-naldemedine were less abundant than those of naldemedine (9% or 13% of AUC of naldemedine) and 16.2% or 18.1% of naldemedine was excreted as unchanged in urine after administration of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine, respectively, and benzamidine was the major radioactive component after administration of [oxadiazole-14C]-naldemedine (32.5% of administered dose). Overall, the recovery of total radioactivity was 92% (57.3% in urine; 34.8% in feces) after administration of [oxadiazole-14C]-naldemedine and 85% (20.4% in urine; 64.3% in feces) after administration of [carbonyl-14C]-naldemedine.4. Our findings suggest that naldemedine is mainly metabolized to nor-naldemedine. Naldemedine was rapidly absorbed and well tolerated, with no major safety signals observed.