{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:21:49Z","timestamp":1760217709163},"reference-count":22,"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>This randomized, double\u2010blind, placebo\u2010controlled, ascending\u2010dose, crossover study evaluated single oral doses of naloxegol (NKTR\u2010118; 8, 15, 30, 60, 125, 250, 500, and 1000\u2009mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol\u2010matching placebo administered with morphine and lactulose in a 2\u2010period crossover design. Periods were separated by a 5\u2010 to 7\u2010day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine\u2010induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose\u2010ordered antagonism of morphine's peripheral gastrointestinal effects. Forty\u2010four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000\u2009mg, indicating negligible antagonism of morphine's CNS effects at doses \u2264\u2009125\u2009mg. Rapid absorption, linear pharmacokinetics up to 1000\u2009mg, and low to moderate between\u2010subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000\u2009mg.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cpdd.206","type":"journal-article","created":{"date-parts":[[2015,6,15]],"date-time":"2015-06-15T23:45:48Z","timestamp":1434411948000},"page":"434-441","source":"Crossref","is-referenced-by-count":20,"title":["Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending\u2010dose study"],"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":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2007.01415.x"},{"issue":"3","key":"e_1_2_8_3_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."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2008.10.008"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.36076\/ppj.2008\/11\/S105"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/11634970-000000000-00000"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.09.019"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2008.00495.x"},{"issue":"8","key":"e_1_2_8_9_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_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0885-3924(01)00369-4"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161212803582388"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp070430"},{"key":"e_1_2_8_13_1","unstructured":"Movantik\u2122 (naloxegol). 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