Open AccessPopulation Exposure‐Response Modeling Supported Selection of Naloxegol Doses in Phase III Studies in Patients With Opioid‐Induced Constipation
Author(s) -
AlHuniti Nidal,
Xu Hongmei,
Zhou Diansong,
Aksenov Sergey,
Fox Robert,
Bui Khanh H.
Publication year - 2017
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12229
Subject(s) - medicine , placebo , discontinuation , population , logistic regression , opioid , anesthesia , alternative medicine , receptor , environmental health , pathology
Naloxegol is approved for the treatment of opioid‐induced constipation (OIC) in adults with chronic noncancer pain. Population exposure‐response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed‐effects logistic regression dose‐response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.