title: Model-based approaches for ivabradine development in paediatric population, part I: study preparation assessment.
abstract: The main objective was to help design a paediatric study for ivabradine, a compound already marketed in adults, focusing on: the paediatric formulation evaluation, the doses to be administered, the sampling design and the sampling technique. A secondary objective was to perform a comparison of the prediction of ivabradine pharmacokinetics (PK) in children using a physiologically-based pharmacokinetic (PBPK) approach and allometric scaling of a population pharmacokinetic (PPK) model. A study was conducted in order to assess the relative bioavailability (Frel) of the paediatric formulation and a similar Frel was observed between the paediatric formulation and the adult marketed tablet. PBPK modelling was used to predict initial doses to be administered in the paediatric study and to select the most appropriate sample time collections. The dried blood spot technique was recommended in the clinical trial in children. Simulations obtained by both the PBPK approach and allometric scaling of a PPK model were compared a posteriori to the paediatric study observations. Both PPK and PBPK approaches allowed an adequate prediction of the PK of ivabradine and its metabolite in children.
authors.affiliation: Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France. sophie.peigne@servier.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Peigné
authors.affiliation: Centre de Pharmacocinétique et Métabolisme, Groupe de Recherche Servier, Orléans, France.
authors.forename: François
authors.initials: F
authors.lastname: Bouzom
authors.affiliation: Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Karl
authors.initials: K
authors.lastname: Brendel
authors.affiliation: Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gesson
authors.affiliation: Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fouliard
authors.affiliation: Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Marylore
authors.initials: M
authors.lastname: Chenel
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000375:Aging / Q000378:metabolism; D001552:Benzazepines / Q000493:pharmacokinetics*; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D059788:Dried Blood Spot Testing; D005260:Female; D006801:Humans; D007223:Infant; D000077550:Ivabradine; D008297:Male; D008954:Models, Biological; D010372:Pediatrics; D011153:Population; D012107:Research Design; D013607:Tablets
chemical_list: D001552:Benzazepines; D002316:Cardiotonic Agents; D013607:Tablets; D000077550:Ivabradine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Allometric scaling; Dried blood spot; Ivabradine; Paediatric; Physiologically-based pharmacokinetic; Study preparation