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

Abstract

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.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

<p>Naldemedine: A New Option for OIBD</p>

“…32 The volume of distribution of naldemedine is 155 L. 26 Naldemedine is mainly metabolized by CYP3A4 to nornaldemedine, via N-dealkylation of the methylcyclopropyl portion of the parent compound: 33 nornaldemedine is responsible for 9-13% of systemic exposure to naldemedine. 32 Naldemedine is also metabolized via glucuronidation through UGT1A3, forming the minor metabolite naldemedine 3-G: this metabolite accounts for about 3% of total exposure to naldemedine. 1,28 Both nornaldemedine and naldemedine 3-G antagonize opioid receptors, but to a lesser extent than the parent compound.…”

“…Conversely, in patients with severe liver failure data are not available, since opioid themselves may worsen this clinical condition. 32…”

The role of naldemedine in the treatment of opioid-induced constipation

“…Wydalanie naldemedyny u chorych z zaburzeniami czynności nerek, w tym w fazie schyłkowej wymagających hemodializy, nie ulega zaburzeniu, a farmakokinetyka jest podobna jak u osób z prawidłową czynnością nerek, u których 16-18% wydalane jest z moczem w formie niezmienionej [16]. Naldemedyna w znikomym stopniu (2,7%) ulega eliminacji podczas hemodializy [17].…”

“…U pacjentów z łagodnymi lub umiarkowanymi zaburzeniami czynności wątroby (klasa A lub B w skali Childa-Pugha) farmakokinetyka naldemedyny jest niezaburzona (nie badano wpływu ciężkiej niewydolności wątroby) [16,17].…”

The role of naldemedine in the treatment of patients with opioid-induced constipation

“…A mild and moderate hepatic impairment does not significantly affect naldemedine pharmacokinetics. However, patients with severe hepatic impairment were not studied, therefore naldemedine is not recommended in this patient group [25].…”