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

Aims: 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. Methods: The models were developed based on data obtained at baseline and following treatment with placebo, nepadutant 0.1 mg/kg or nepadutant 0.5 mg/kg administered for 7 days. A continuous response variable, duration of crying and fussing in minutes within 2 h interval, was assembled based on records from "baby's day" diary. Results: 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 5.3 kg, the estimated apparent clearance was 68.6 L/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 4 a.m. and 9 p.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 0.5 mg/kg. Conclusions: Population pharmacokinetic and dose–response models were successfully developed characterizing the available nepadutant pharmacokinetics and duration of crying and fussing data in infants. [ABSTRACT FROM AUTHOR]