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Lockwood2006_PKPD_AlzheimersDisease

  public model
Short description

This a model from the article:
Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease.
Lockwood P, Ewy W, Hermann D, Holford N. Pharm Res2006 Sep;23(9):2050-9 16906456,
Abstract:
OBJECTIVE: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials. MATERIALS AND METHODS: A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability. CONCLUSION: CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial.

This model was taken from the CellML repository and automatically converted to SBML.
The original model was: Lockwood P, Ewy W, Hermann D, Holford N. (2006) - version=1.0
The original CellML model was created by:
James Lawson
j.lawson@auckland.ac.nz
The University of Auckland

Format
SBML (L2V4)
Related Publication
  • Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease.
  • Lockwood P, Ewy W, Hermann D, Holford NH
  • Pharmaceutical research , 9/ 2006 , Volume 23 , Issue 9 , pages: 2050-2059
  • Pfizer Global Research and Development, Ann Arbor, Michigan, USA. peter.lockwood@pfizer.com
  • Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025).A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability.CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial.
Contributors
administrator, Camille Laibe

Metadata information

Curation status
Non-curated
Name Description Size Actions

Model files

MODEL1006230054.xml.origin SBML L2V4 representation of Lockwood2006_PKPD_AlzheimersDisease 10.47 KB Preview | Download

  • Model originally submitted by : Camille Laibe
  • Submitted: Jun 23, 2010 10:12:15 AM
  • Last Modified: Feb 14, 2018 3:54:56 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Feb 14, 2018 3:54:56 PM
    • Submitted by: administrator
    • With comment: Current curated version of Lockwood2006_PKPD_AlzheimersDisease
  • Version: 2 public model Download this version
    • Submitted on: Jun 25, 2010 2:17:54 PM
    • Submitted by: Camille Laibe
    • With comment: Current version of Lockwood2006_PKPD_AlzheimersDisease
  • Version: 1 public model Download this version
    • Submitted on: Jun 23, 2010 10:12:15 AM
    • Submitted by: Camille Laibe
    • With comment: Original import of Lockwood2006_PKPD_AlzheimersDisease
Curator's comment:
(added: 01 Mar 2018, 15:28:59, updated: 01 Mar 2018, 15:28:59)
Similar figures of figure 1 of the reference publication have been produced. Raw ADAS-cog scores have been plotted for varied CeA (CI-1017) concentration using a linear (top left), hyperbolic (top right) and signmoidal (bottom left) response model. Simulations were performed in COPASI 4.22 (Build 170) and figures were generated with MATLAB R2014. Different response models can be implemented by changing the quantity 'MODEL_TYPE' from 0 to 4 with 0=Inactive, 1=Linear, 2=Hyperbolic, 3=Sigmoidal, 4=U-Shaped. Simulations were performed using a parameter scan varying the initial value of CeA from 0 to 75 in increments of 1 with the parameter scan task set to 'time course' and plot type set to 'points'.