title: The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol.
abstract: The impact of renal impairment on the pharmacokinetics of a 25-mg oral dose of naloxegol was examined in patients with renal impairment classified as moderate, severe, or end-stage renal disease (ESRD) and compared with healthy subjects (n = 8/group). Geometric mean area under the plasma concentration-time curve (AUC) was increased in patients with moderate (1.7-fold) or severe (2.2-fold) impairment, and maximum plasma concentrations (Cmax ) were elevated in patients with moderate (1.1-fold) or severe (1.8-fold) impairment. These findings were driven by higher exposures in two patients in each of the moderate and severe impairment groups; exposures in all other patients were similar to the control group. Overall exposures in ESRD patients were similar and Cmax was 29% lower versus normal subjects. Renal impairment minimally affected other plasma pharmacokinetic parameters. As renal clearance was a minor component of total clearance, exposure to naloxegol was unaffected by the degree of renal impairment, with no correlation between either AUC or Cmax and estimated glomerular filtration rate (eGFR). Hemodialysis was an ineffective means to remove naloxegol. Naloxegol was generally well tolerated in all groups. Renal impairment could adversely affect clearance by hepatic and gut metabolism, resulting in the increased exposures observed in outliers of the moderate and severe renal impairment groups.
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Bui
authors.forename: Fahua
authors.initials: F
authors.lastname: She
authors.forename: Mark
authors.initials: M
authors.lastname: Sostek
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics*; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D009019:Morphinans; D009292:Narcotic Antagonists; D011092:Polyethylene Glycols; C000589308:naloxegol
keywords: naloxegol; opioid receptor antagonist; opioid-induced constipation; pharmacokinetics; renal impairment