The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Naldemedine is a peripherally acting μ‐opioid‐receptor antagonist for the treatment of opioid‐induced constipation. Two phase 1 single‐dose studies investigated the pharmacokinetics and safety of a 0.2‐mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end‐stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration‐time curve (AUC(0‐inf)) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC(0‐inf) ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.