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

Aims

Naloxegol, 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).

Methods

Analysis included 12 844 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.

Results

The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (k_a1 4.56 h⁻¹) and one more complex absorption with a transit compartment (k_tr 2.78 h⁻¹). Mean (SE) parameter estimates for CL/F and V_c/F, the parameters assessed for covariate effects, were 115 (3.41) l h^–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.

Conclusions

Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.