Lockwood2006 - Alzheimer's Disease PBPK model
This model is described in the article:
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.
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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 , PubMed ID: 16906456
- 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.
Submitter of this revision: administrator
Modellers: administrator, Camille Laibe
Metadata information
isDescribedBy (2 statements)
hasPart (1 statement)
isVersionOf (1 statement)
occursIn (1 statement)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
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Model files |
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| BIOMD0000000673_url.xml | SBML L2V4 representation of Lockwood2006 - Alzheimer\s Disease PBPK model | 63.23 KB | Preview | Download |
Additional files |
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| BIOMD0000000673-biopax2.owl | Auto-generated BioPAX (Level 2) | 3.67 KB | Preview | Download |
| BIOMD0000000673-biopax3.owl | Auto-generated BioPAX (Level 3) | 3.70 KB | Preview | Download |
| BIOMD0000000673.m | Auto-generated Octave file | 6.33 KB | Preview | Download |
| BIOMD0000000673.pdf | Auto-generated PDF file | 145.98 KB | Preview | Download |
| BIOMD0000000673.png | Auto-generated Reaction graph (PNG) | 4.27 KB | Preview | Download |
| BIOMD0000000673.sci | Auto-generated Scilab file | 154.00 Bytes | Preview | Download |
| BIOMD0000000673.svg | Auto-generated Reaction graph (SVG) | 845.00 Bytes | Preview | Download |
| BIOMD0000000673.vcml | Auto-generated VCML file | 22.17 KB | Preview | Download |
| BIOMD0000000673.xpp | Auto-generated XPP file | 5.03 KB | Preview | Download |
| BIOMD0000000673_urn.xml | Auto-generated SBML file with URNs | 63.18 KB | Preview | Download |
| MODEL1006230054_edited.cps | A parameter scan will produce similar figures to figure 1 of the reference publication. 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. | 56.42 KB | Preview | Download |
| MODEL1006230054_edited.sedml | A parameter scan will produce a similar figure to figure 1 (Sigmoidal response model, bottom left) of the reference publication. 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. | 3.91 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
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Version: 3
- Submitted on: Feb 14, 2018 3:54:56 PM
- Submitted by: administrator
- With comment: Current curated version of Lockwood2006_PKPD_AlzheimersDisease
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Version: 2
- Submitted on: Jun 25, 2010 2:17:54 PM
- Submitted by: Camille Laibe
- With comment: Current version of Lockwood2006_PKPD_AlzheimersDisease
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Version: 1
- Submitted on: Jun 23, 2010 10:12:15 AM
- Submitted by: Camille Laibe
- With comment: Original import of Lockwood2006_PKPD_AlzheimersDisease
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(added: 01 Mar 2018, 15:28:59, updated: 01 Mar 2018, 15:28:59)