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

Trial design and analysis

Specific populations

Pharmacometrics

Gastroenterology

Br J Clin Pharmacol. 2024 Sep 26. Online ahead of print.

Jönsson S, Bouchene S, Mazzei P, Borella E, Piana C, Tagliavini A, Koletzko S, Werkstetter K, Capriati A, Pellacani A, Karlsson MO, Jonsson EN

Current treatments in infantile colic are insufficient, with inadequate efficacy or intolerable side-effects. Nepadutant, a tachykinin NK₂ receptor antagonist, was considered a promising candidate through its mechanism of action and for its potential to be dosed orally in infants. In a new publication the pharmacokinetics and exposure–response (duration of crying and fussing) following treatment with nepadutant were described in infants (4-20 weeks) with colic. The continuous response variable, duration of crying and fussing in minutes within 2 h interval, was assembled based on records from "Baby's day Diary©".

Performing clinical studies in infants involves challenges, such as imprecision in oral dose administration and the sparse blood sampling demanded for pharmacokinetic observations. Furthermore, capturing the babies' behaviors on a 24 h basis in 5-minute increments resulted in very rich data. Therefore, the analyses required to manage the uncertainties and data characteristics. For example, spitting was explored as a covariate on bioavailability to explain variability. Also, an approach to reduce the rich response data while keeping sufficient dissolution to capture variations over time was developed resulting in the variable ‘duration of crying and fussing per 2 h’.

It was found that nepadutant was absorbed in infants following oral administration but exhibiting large inter-subject variability. The circadian rhythm and the duration of crying and fussing was characterized with the lowest and maximum duration occurring at 4 a.m. and 9 p.m., respectively. The placebo effect was time dependent and a statistically significant (P < .01) effect of nepadutant dose was established.

This analysis provides an illustrative example involving an interesting response variable for which the baseline, placebo and drug treatment responses were disentangled and described in a model that can be used for simulations of alternative dose regimens.