N. Al-Huniti,1 H. Xu,1 D. Zhou,1 K. H. Bui2; 1AstraZeneca, Waltham, MA, 2AstraZeneca, Wilmington, DE
BACKGROUND: Establish a quantitative decision making framework to support phase II and III clinical development of Naloxegol for the treatment of opioid-induced constipation (OIC) in patients with non-cancer pain.
METHODS: A population pharmacokinetic (PK) model was developed using 11 phase I studies, one phase II study and two phase III studies. An integrated model for dropout and responder rate based phase II data was developed. Exposure-efficacy model integrating dropouts was developed using spontaneous bowel movements (SBM) data from 1,331 patients with OIC in two phase III pivotal trials. Number of SBMs was characterized by a longitudinal non-linear mixed-effects logistic regression dose-response model. Dropout (incidence of diary entry discontinuation) was described by a time-to-event model. Simulation from the exposure-response model was then performed to predict responder rate.
RESULTS: PK of naloxegol is described by a linear, two-compartment disposition model with dual parallel first-order absorptions and first-order elimination. The integrated model for dropout and responder rate described Phase II data very well and provided a benefit-risk assessment for phase III dose selection. Dropout and SBM models described phase III data well and established a quantitative framework to support the benefit profile
for phase III doses. Weak opioid usage at baseline was identified as an important covariate for the SBM model. 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.
CONCLUSION: Model-based simulations suggest that doses of 12.5 mg and higher provide a promising clinical benefit over placebo. The analysis supported Naloxegol clinical dose selection and development decisions.