Designing More Efficient Preclinical Experiments: A Simulation Study in Chemotherapy-Induced Myelosupression

Abstract

A newmore 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 fromthemain study animals, taking nomore than one sample in 24h 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-inducedmyelosupression in rats. Data sets were simulated froma 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 neutrophilmodels 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 tomodel the data. If large IOV is suspected, caution should be exercised to avoid parameter estimation bias, and inflation of variability and residual error.