Sophie Peigné, Sylvain Fouliard and Marylore Chenel
Department of Clinical Pharmacokinetics, Institut de Recherches Internationales Servier
Introduction: A study was conducted in paediatric patient population with drug S (marketed in adult), 80 % metabolized via CYP3A4. The objectives of this study were to describe the PK of drug S and its active metabolite in this population, to assess potential differences in PK between age classes, and to assess whether the blood/plasma ratio and the PKPD relationship are preserved between paediatric and adult populations.
Methods: The clinical study included a first titration period that should ensure that children started with a safe dose but were up titrated as rapidly as possible to an effective dose.PK data were obtained after 5 blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. PK measurements were available for 70 patients.To describe drug S and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects.Plasma PK exposure parameters were calculated in children using converted plasma PK profiles. To assess the PKPD relationship in children, a former adult PKPD model was used.
Results: Relationship between blood and plasma concentration was described using linear mixed effect models. 2- and 1- compartment models best described parent and metabolite dispositions, respectively. A first pass effect and the formation of the metabolite from the circulating drug S were included.Weight effects were fixed to the allometric values of 0.75 and 1 on CL and V, respectively [1]. In addition, a maturation function was added on metabolite formation clearance reflecting CYP3A4 enzyme maturation [2]. Other maturation processes that were investigated did not result in fit improvement.Plasma PK exposure comparison indicated that higher dose/kg were necessary to have similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose.Simulations were performed using adult PKPD model and individual plasma PK parameters and showed that the PKPD relationship in adult patients is conserved in children.
Conclusions: This work underlines the importance of modelling and simulations for the analysis of clinical studies for drug development in pediatric populations. The assessment of PK and PKPD relationship in children through the use of integrated analysis tools allowed to draw conclusions regarding the effects of dug S in children.
References:
[1] Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25-36.
[2] Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931-56.
Reference: PAGE 24 () Abstr 3353 [www.page-meeting.org/?abstract=3353]
Poster: Drug/Disease modeling - Paediatrics