DDMODEL00000239: Daily and aggregated seizure counts model for scaling from adults to children in epilepsy

  public model
Short description:
Daily and aggregated seizure counts model using negative binomial model with Markovian influence of previous day seizure count and mixture model for responder and placebo-type patients for scaling from adults to children in epilepsy
Original code
  • Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children
  • Rik Schoemaker(1,3), Armel Stockis(2)
  • PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe, 6/2016, Volume 25, pages: Abstr 5752
  • (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 [1], 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. References: [1] Ahn JE, Plan EL, Karlsson MO and Miller R. Modeling Longitudinal Daily Seizure Frequency Data From Pregabalin Add-On Treatment. J Clin Pharmacol 2012 52: 880-892.
Rik Schoemaker
Context of model development: Disease Progression model; Patient Population Selection and Bridging between Population (Pediatrics, Elderly, Obese);
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: 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 16 years, LEV data were modelled and used to scale the existing adult model for BRV to children. The model described seizure counts using a negative binomial distribution taking previous day seizure frequencies into account [1], and using a mixture model to separate a 'placebo like' and a 'responder' sub-population. The model was adapted to describe aggregated monthly seizure counts for the adult subjects in the LEV trials: daily seizure counts were only available for the children in the LEV trials. 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. For LEV, 33.5% of subjects were estimated to be in the 'mixture model responders' sub-population. 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. References: [1] Ahn JE, Plan EL, Karlsson MO and Miller R. Modeling Longitudinal Daily Seizure Frequency Data From Pregabalin Add-On Treatment. J Clin Pharmacol 2012 52: 880-892.;
Modelling task in scope: simulation; estimation;
Nature of research: Clinical research & Therapeutic use; Approval phase/Registration trial (Phase III); Early clinical development (Phases I and II);
Therapeutic/disease area: CNS;
Annotations are correct.
This model is not certified.
  • Model owner: Rik Schoemaker
  • Submitted: May 15, 2017 5:14:30 PM
  • Last Modified: May 15, 2017 5:14:30 PM
Revisions
  • Version: 12 public model Download this version
    • Submitted on: May 15, 2017 5:14:30 PM
    • Submitted by: Rik Schoemaker
    • With comment: Updated model annotations.
 
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