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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 Res 2006 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

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..

To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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
Curated
Original model(s)
http://models.cellml.org/exposure/60366c003dba765e53609eaca35027fd
Name Description Size Actions

Model files

MODEL1006230054_url.xml SBML L2V4 representation of Lockwood2006_PKPD_AlzheimersDisease 16.25 KB Preview | Download

Additional files

MODEL1006230054.png Auto-generated Reaction graph (PNG) 5.04 KB Preview | Download
MODEL1006230054-biopax3.owl Auto-generated BioPAX (Level 3) 2.01 KB Preview | Download
MODEL1006230054_urn.xml Auto-generated SBML file with URNs 17.61 KB Preview | Download
MODEL1006230054.sci Auto-generated Scilab file 252.00 bytes Preview | Download
MODEL1006230054-biopax2.owl Auto-generated BioPAX (Level 2) 1.06 KB Preview | Download
MODEL1006230054.pdf Auto-generated PDF file 151.12 KB Preview | Download
MODEL1006230054.m Auto-generated Octave file 3.84 KB Preview | Download
MODEL1006230054.xpp Auto-generated XPP file 2.92 KB Preview | Download
MODEL1006230054.svg Auto-generated Reaction graph (SVG) 851.00 bytes Preview | Download
MODEL1006230054.vcml Auto-generated VCML file 900.00 bytes 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'.