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

Abstract

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.

Figure 1

Diagnostic plots for the final model of naloxegol: (A) observed vs. individual predicted, (B) observed vs. population predicted, (C) individual predicted vs. population conditional weighted residuals, (D) population predicted vs. individual weighted residuals, (E) subject identification vs. population conditional weighted residuals and (F) time since last dose vs. individual weighted residuals. CWRES, population conditional weighted residuals; IPRED, individual predicted; IWRES, individual weighted residuals; PRED, population predicted; ID, identification

Figure 2

Naloxegol plasma concentration vs. time profiles (posterior predictive check from final model) for phase 1 studies (A), phase 2b sub‐study (B) and two phase 3 studies (C), at the 25 mg once daily dose. Grey open circles represent observed individual data; black filled circles represent observed geometric mean data. LLOQ, lower limit of quantitation. ‐‐‐‐ Observed median and 90% CI, — Predicted median and 90% PI

Figure 3

Forest plots showing the effect of covariates on (A) AUC and (B) C _max of naloxegol (point estimate and 90% PI). Dashed lines represent (80%, 125%) interval. ALT, alanine aminotransferase; AUC, area under the plasma concentration vs. time curve; C _max, maximum plasma concentration; CL_cr, creatinine clearance; CYP3A4, cytochrome P450 3A4; P‐gp, P‐glycoprotein; PI, prediction interval; SD, standard deviation