Search

The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma PK exposure parameters were calculated in children using plasma PK profiles. In order to assess the PK/PD relationship in children, an adult PK/PD model was used. The relationship between blood and plasma concentrations was described using linear mixed effect models. Two and one-compartment models best described parent and metabolite dispositions. Weight effects were fixed to the allometric values of ¾ on clearance (CL) and 1 on volume. A maturation function was added on metabolite formation clearance (CL PM ) reflecting enzyme maturation. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose. The PK/PD relationship in adult patients is conserved in children.

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.