Population pharmacokinetic and dose-response models of nepadutant, a selective antagonist of the NK2 receptors, in infants with colic.

Abstract

The aim of the current analyses was to develop a population pharmacokinetic model for nepadutant in infants with colic, and a pharmacokinetic-pharmacodynamic model based on observations of duration of crying and fussing following oral nepadutant administration in infants (3-25 weeks) with colic. The models were developed based on data obtained at baseline and following treatment with placebo, nepadutant 0.1mg/kg or nepadutant 0.5mg/kg administered for 7days. A continuous response variable, duration of crying and fussing in minutes within 2h interval, was assembled based on records from "baby's day" diary. The pharmacokinetics of nepadutant was described by a one-compartment model with first-order absorption and elimination with body weight as a structural covariate incorporated allometrically. For an infant weighing 5.3kg, the estimated apparent clearance was 68.6L/h (12% relative standard error) and exhibited large variability (78% coefficient of variation). The pharmacokinetic-pharmacodynamic model described (i) a circadian rhythm in the response with lowest and highest observations at 4a.m. and 9p.m., respectively, (ii) a placebo effect increasing and flattening out with time in an exponential manner, and (iii) a statistically significant (P < .01) linearly increasing response with dose. The observed and model predicted relative change in response from baseline was -35% and -28% (95% prediction interval -36%; -19%) following placebo, and -44% and -36% (-46%; -27%) after 0.5mg/kg. Population pharmacokinetic and dose-response models were successfully developed characterizing the available nepadutant pharmacokinetics and duration of crying and fussing data in infants.