PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 25 (2016) Abstr 5752 [www.page-meeting.org/?abstract=5752]
Oral: Other Topics
Rik Schoemaker(1,3), Armel Stockis(2)
(1) SGS Exprimo, (2) UCB Pharma, (3) Current affiliation: Occams
Objectives: To scale an existing adult population PK/PD model for brivaracetam (BRV) into children, using a combined adult-pediatric PK/PD model for levetiracetam (LEV), a compound with a similar primary mechanism of action, and to predict the effective dose of BRV in children aged 4 to 16 years.
Methods: A population PK/PD model has been previously developed to describe the relationship between BRV plasma concentrations and seizure frequency change from baseline in adult subjects. A pediatric population PK model is available for BRV. For LEV, both PK and PD data are available in adults and children. In order to support the extrapolation of PD in BRV to children aged ≥4 to
The model described seizure counts using a negative binomial distribution taking previous day seizure frequencies into account , and using a mixture model to separate a 'placebo like' and a 'responder' sub-population.
VPCs were used to ascertain the ability of the LEV adult/pediatric PK/PD model to adequately simulate trial outcome in terms of percentage change in seizure frequency from baseline, and fraction of subjects with ≥50% decrease in seizure frequency. PK and PD simulations for BRV were performed in children for a range of mg/kg doses to predict BRV effect in pediatric subjects, and aid trial design decisions.
Results: The LEV PK/PD model was able to describe both the adult and the pediatric data using the same drug effect population parameters, and using a model structure very similar to the existing adult PK/PD BRV model. VPCs illustrated that the LEV adult/pediatric PK/PD model was capable of simulating the observed trial outcomes. Simulation with the adult BRV PK/PD model in combination with the pediatric BRV population PK model, allowed characterization of the dose-response curve, suggesting maximum reponse at BRV 4 mg/kg/day dosing in children.
Conclusions: Application of a population PK/PD count model to trial data from a registered compound with a similar primary mechanism of action, allowed prediction of drug effects in pediatric patients for BRV that will help plan future studies.