Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients

AimsNaloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (V-c/F). MethodsAnalysis included 12844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. ResultsThe final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (k(a1) 4.56h(-1)) and one more complex absorption with a transit compartment (k(tr) 2.78h(-1)). Mean (SE) parameter estimates for CL/F and V-c/F, the parameters assessed for covariate effects, were 115 (3.41) lh(-1) and 160 (27.4) l, respectively. Inter-individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P-glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure. ConclusionsAdministration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.