Pharmacologic Profile of Naloxegol, a Peripherally Actingµ-Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation.
Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind toµ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally actingµ-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 humanµ-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 30μM 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 theµ-opioid receptor in the ENS while preserving CNS-mediated analgesia.
AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.).
Eike
E
Floettmann
AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.) Khanh.Bui@astrazeneca.com.
Khanh
K
Bui
AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.).
Mark
M
Sostek
AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.).
Kemal
K
Payza
AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.).
Michael
M
Eldon
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009019:Morphinans / Q000493:pharmacokinetics / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology / Q000633:toxicity; D053610:Opiate Alkaloids / Q000494:pharmacology / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D000701:Analgesics, Opioid; D009019:Morphinans; D053610:Opiate Alkaloids; D017450:Receptors, Opioid, mu; D011092:Polyethylene Glycols; C000589308:naloxegol; D009020:Morphine