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

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 T_max of approximately 0.8-0.9 h and a geometric mean t_1/2,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.