Population pharmacokinetic and dose-response models of nepadutant, a selective antagonist of the NK 2 receptors, in infants with colic

• Published in: British journal of clinical pharmacology 2024-09
• Main Authors: Jönsson, Siv, Bouchene, Salim, Mazzei, Paolo, Borella, Elisa, Piana, Chiara, Tagliavini, Alessia, Koletzko, Sibylle, Werkstetter, Katharina, Capriati, Angela, Pellacani, Andrea, Karlsson, Mats O, Jonsson, E Niclas
• Format: Article
• Language: English
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.16230

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 0.1 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. 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