title: Designing More Efficient Preclinical Experiments: A Simulation Study in Chemotherapy-Induced Myelosupression.
abstract: A new more efficient preclinical study design (referred to as a compact design) is proposed that removes the need for satellite animals for the collection of toxicokinetic (TK) data by sampling from the main study animals, taking no more than one sample in 24 h to build up a full profile over the course of the study. The compact design's performance was tested with a simulation study, using an example of chemotherapy-induced myelosupression in rats. Data sets were simulated from a model based on available data, following both the compact design and a traditional design using satellite animals, with 100 studies being simulated for each. The effect of the compact design on parameter and variance estimates for the TK and neutrophil models were investigated, as well as the potential effect of interoccasion variability (IOV). The compact design performed equally as well as the traditional design, and had little impact on parameter or variation estimates, indicating that it would be a suitable alternative to traditional satellite designs while reducing the number of animals required. When IOV was present but not accounted for during the TK analysis some parameter estimates were biased and interindividual variation and residual errors inflated; this was reduced by allowing for IOV in the analysis. Using the compact design removes the need for a satellite group, reducing the number of animals required, without affecting the ability to model the data. If large IOV is suspected, caution should be exercised to avoid parameter estimation bias, and inflation of variability and residual error.
authors.affiliation: *Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, the University of Manchester, M13 9PT, United Kingdom and emma.martin@manchester.ac.uk.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Martin
authors.affiliation: *Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, the University of Manchester, M13 9PT, United Kingdom and.
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
authors.affiliation: AstraZeneca, Innovative Medicines, Oncology, Modelling and Simulation, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom.
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015507:Drugs, Investigational / Q000633:toxicity*; D005260:Female; D008297:Male; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D012107:Research Design
chemical_list: D015507:Drugs, Investigational
keywords: 3Rs; pharmacodynamics; preclinical study design; toxicokinetics