Abstract
Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human µ-opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were <10% up to 30 μM and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15-fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the µ-opioid receptor in the ENS while preserving CNS-mediated analgesia.
Footnotes
- Received November 29, 2016.
- Accepted March 8, 2017.
This study and editorial support of this publication were funded by AstraZeneca Pharmaceuticals LP (Wilmington, DE).
Part of this work was previously presented as an oral presentation: Tack J, Cimen A, Bui K, Sostek M (2015). Naloxegol for opioid-induced constipation: mechanism of action and clinical implications. United European Gastroenterol J 3:A20.
Part of this work was previously presented as a poster: Eldon MA, Song D, Neumann TA, Wolff R, Cheng L, Viegas TX, Bentley MD, Fishburn CS, Kugler AR (2007). NKTR-118 (oral PEG-naloxol), a PEGylated derivative of naloxone: demonstration of selective peripheral opioid antagonism after oral administration in preclinical models. American Academy of Pain Management 18th Annual Clinical Meeting; 2007 Sep 27–30; Las Vegas, NV.
Part of this work was previously presented as a poster: Tack J, Cimen A, Bui K, Sostek M (2016). Naloxegol for opioid-induced constipation: mechanism of action and clinical implications. Gastroenterology 150 (Suppl 1):S538.
↵1 Current affiliation: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts.
↵2 Current affiliation: Pfizer, Collegeville, Pennsylvania.
↵3 Current affiliation: NEOMED Institute, Saint-Laurent, Quebec, Canada.
- Copyright © 2017 The Author(s).
This is an open access article distributed under the CC BY Attribution 4.0 International license.