title: A latent pharmacokinetic time profile to model dose-response survival data.
abstract: 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.
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Universiteit Hasselt, Diepenbeek, Belgium. tom.jacobs@uhasselt.be
authors.forename: Tom
authors.initials: T
authors.lastname: Jacobs
authors.forename: Roel
authors.initials: R
authors.lastname: Straetemans
authors.forename: Geert
authors.initials: G
authors.lastname: Molenberghs
authors.forename: J
authors.initials: J
authors.lastname: Adriaan Bouwknecht
authors.forename: Luc
authors.initials: L
authors.lastname: Bijnens
mesh_terms: D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D003913:Dextroamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis; D016013:Likelihood Functions; D016014:Linear Models; D051379:Mice; D015233:Models, Statistical; D009048:Motor Skills / Q000187:drug effects; D010599:Pharmacokinetics; D010622:Phencyclidine / Q000493:pharmacokinetics / Q000494:pharmacology; D045442:Rotarod Performance Test; D016019:Survival Analysis
chemical_list: D010622:Phencyclidine; D003913:Dextroamphetamine