title: Population Exposure-Response Modeling of Naloxegol in Patients With Noncancer-Related Pain and Opioid-Induced Constipation.
abstract: Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: N
authors.initials: N
authors.lastname: Al-Huniti
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Nielsen
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hutmacher
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lappalainen
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cantagallo
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sostek
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects*; D059350:Chronic Pain / Q000188:drug therapy* / Q000453:epidemiology; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003248:Constipation / Q000139:chemically induced* / Q000188:drug therapy* / Q000453:epidemiology; D003672:Defecation / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008499:Medical Records / Q000706:statistics & numerical data; D008875:Middle Aged; D015233:Models, Statistical; D009019:Morphinans / Q000494:pharmacology / Q000627:therapeutic use*; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; D009292:Narcotic Antagonists; D011092:Polyethylene Glycols; C000589308:naloxegol