Population exposure-response modeling of oral nepadutant administration in infants with colic
P. Mazzei (1), E. Mezzalana (1), G. Smania (1), E.N. Jonsson (2), S. Jönsson (2), S Bouchene (2), M.O. Karlsson (2), S. Scartoni (1), A. Capriati (1)
(1) Menarini Ricerche S.p.A., Florence (Italy), (2) Pharmetheus AB, Uppsala (Sweden)
Objectives: Nepadutant is a potent antagonist of tachykinin NK2 receptors found to control the gastrointestinal hypermotility. In NIC-03, a phase IIa multicentre, randomised, double-blind, placebo controlled trial to study the efficacy of two oral nepadutant doses (0.1 or 0.5 mg/kg) in infants with colic, a population Exposure-Response (ER) analysis was performed. This analysis aimed to: i) develop an ER model based on observations of crying+fussing time and the previously developed population pharmacokinetic model ii) use the ER model to illustrate the performance of the studied dosing regimens in different body weight (WT) groups.
Methods: The population ER model was based on observations of length of crying+fussing time (min) within 2h intervals at baseline (72h prior dosing) as well as while on treatment (last 72h over 1 week placebo and nepadutant treatments). The model described i) the circadian rhythm in the response by the use of sum of cosine functions, ii) the increasing placebo effect versus time with an exponential time dependent model and iii) the increasing response with dose by a linear dose-response model. The effects of WT and AGE were assessed as continuous covariates on parameters of each sub-model. Final analysis dataset included 9945 observations of crying+fussing time/2h from 104 infants. Analyses were conducted using non-linear mixed-effects modelling as implemented in NONMEM [1].
Results: The inclusion of the linear dose-response relationship on top of the placebo model provided a statistically significant improvement in the description of data (p<0.01). The model predicted a change from baseline for the 0.5 mg/kg group of -36%, corresponding to a relative improvement of 29% over placebo. No statistically significant effect of AGE or WT was identified.
Conclusion: According to simulations, the population ER model well described the data and provided further support to the clinical efficacy data favouring nepadutant 0.5 mg/kg dose.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.