{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T15:03:53Z","timestamp":1778684633937,"version":"3.51.4"},"reference-count":15,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,9,4]],"date-time":"2015-09-04T00:00:00Z","timestamp":1441324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Opioid\u2010induced constipation (OIC) is the most common and often a treatment\u2010limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR\u2010118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double\u2010blind, placebo\u2010controlled, multiple\u2010dose, dose\u2010escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice\u2010daily naloxegol solution (25, 60, 125, and 250\u2009mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250\u2009mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cpdd.204","type":"journal-article","created":{"date-parts":[[2015,6,15]],"date-time":"2015-06-15T23:46:10Z","timestamp":1434411970000},"page":"442-448","source":"Crossref","is-referenced-by-count":9,"title":["Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol"],"prefix":"10.1002","volume":"4","author":[{"given":"Michael A.","family":"Eldon","sequence":"first","affiliation":[{"name":"Nektar Therapeutics San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan R.","family":"Kugler","sequence":"additional","affiliation":[{"name":"AstraZeneca Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Medve","sequence":"additional","affiliation":[{"name":"Nektar Therapeutics San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khanh","family":"Bui","sequence":"additional","affiliation":[{"name":"AstraZeneca Wilmington DE USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Butler","sequence":"additional","affiliation":[{"name":"AstraZeneca Wilmington DE USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Sostek","sequence":"additional","affiliation":[{"name":"AstraZeneca Gaithersburg MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,9,4]]},"reference":[{"issue":"3","key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.5055\/jom.2009.0015","article-title":"Opioid\u2010induced bowel dysfunction in cancer\u2010related pain: causes, consequences, and a novel approach for its management","volume":"5","author":"Holzer P","year":"2009","journal-title":"J Opioid Manag."},{"issue":"8","key":"e_1_2_8_3_1","first-page":"1347","article-title":"Management of common opioid\u2010induced adverse effects","volume":"74","author":"Swegle JM","year":"2006","journal-title":"Am Fam Physician."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.09.019"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2007.01.017"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2007.01415.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2008.00495.x"},{"key":"e_1_2_8_8_1","unstructured":"Movantik\u2122 (Naloxegol). Full prescribing information Wilmington DE: AstraZeneca Pharmaceuticals LP;2015."},{"key":"e_1_2_8_9_1","unstructured":"EldonMA SongD NeumannTA et al. NKTR\u2010118 (oral PEG\u2010naloxol) a PEGylated derivative of naloxone: demonstration of selective peripheral opioid antagonism after oral administration in preclinical models [poster 28]. Presented at: 18th Annual Clinical Meeting of the American Academy of Pain Management September 27\u201330 2007; Las Vegas NV."},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2011.30"},{"key":"e_1_2_8_11_1","doi-asserted-by":"crossref","unstructured":"EldonME KuglerAR MedveR et al. Safety tolerability pharmacokinetics and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: a single ascending\u2010dose study.Clin Pharmacol Drug Dev.2015:doi10.1002\/cpdd.206","DOI":"10.1002\/cpdd.206"},{"key":"e_1_2_8_12_1","unstructured":"Data on File. 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