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

Br J Clin Pharmacol. 2016 Jan;81(1):89-100. doi: 10.1111/bcp.12756. Epub 2015 Oct 27.


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 (Vc /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 (ka1 4.56 h(-1) ) and one more complex absorption with a transit compartment (ktr 2.78 h(-1) ). Mean (SE) parameter estimates for CL/F and Vc /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.

Keywords: NKTR-118; naloxegol; nonmem; pharmacokinetics.

MeSH terms

  • Adult
  • Area Under Curve
  • Cytochrome P-450 CYP3A / physiology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Morphinans / pharmacokinetics*
  • Narcotic Antagonists / pharmacokinetics*
  • Polyethylene Glycols / pharmacokinetics*


  • Morphinans
  • Narcotic Antagonists
  • Polyethylene Glycols
  • naloxegol
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human