title: The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.
abstract: Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, MA, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Bui
authors.affiliation: AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA.
authors.forename: Fahua
authors.initials: F
authors.lastname: She
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, MA, USA.
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, MA, USA.
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Huniti
authors.affiliation: AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sostek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects; D019540:Area Under Curve; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D009019:Morphinans / Q000493:pharmacokinetics*; D009020:Morphine / Q000009:adverse effects / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011802:Quinidine / Q000009:adverse effects* / Q000627:therapeutic use; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D009019:Morphinans; D017450:Receptors, Opioid, mu; D011092:Polyethylene Glycols; C000589308:naloxegol; D009020:Morphine; D011802:Quinidine
keywords: P-glycoprotein; blood-brain barrier; cytochrome P450 3A4; drug-drug interactions; morphine; naloxegol; quinidine