Population Exposure‐Response Modeling Supported Selection of Naloxegol Doses in Phase III Studies in Patients With Opioid‐Induced Constipation

摘要

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.