A Latent Pharmacokinetic Time Profile to Model Dose-Response Survival Data

The accelerating rotarod test is a preclinical pharmacodynamic test to assess the effect of a treatment on an animal's motor coordination. Two models are proposed to analyze the dose-response time-to-event data that typically result from such experiments: (1) a linear regression model and (2) a...

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Bibliographic Details
Published in:Journal of biopharmaceutical statistics 2010-07, Vol.20 (4), p.759-767
Main Authors: Jacobs, Tom, Straetemans, Roel, Molenberghs, Geert, Adriaan Bouwknecht, J., Bijnens, Luc
Format: Article
Language:English
Subjects:
Accelerated failure time
Accelerating rotarod
Algorithms
Animals
Computer Simulation
Dextroamphetamine - pharmacokinetics
Dextroamphetamine - pharmacology
Dose-response
Dose-Response Relationship, Drug
Drug-Related Side Effects and Adverse Reactions - diagnosis
K-PD model
Likelihood Functions
Linear Models
Mice
Models, Statistical
Motor ability
Motor Skills - drug effects
Pharmacokinetics
Pharmacology
Phencyclidine - pharmacokinetics
Phencyclidine - pharmacology
Rodents
Rotarod Performance Test
Simulation
Statistics
Studies
Survival
Survival Analysis
Test methods
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Summary:The accelerating rotarod test is a preclinical pharmacodynamic test to assess the effect of a treatment on an animal's motor coordination. Two models are proposed to analyze the dose-response time-to-event data that typically result from such experiments: (1) a linear regression model and (2) an E max model with latent drug concentration at the site of action. Both cope with the survival character of the data. The latter model allows a direct comparison of compounds, but raises the question of whether the study design would benefit from the inclusion of additional mice for plasma concentration sampling on the one hand or whether additional time-to-event data without plasma concentration sampling should be ascertained from these additional mice on the other hand. A simulation study explores the impact on operational characteristics of this change of study design.
ISSN:1054-3406
1520-5711
DOI:10.1080/10543401003618249