Teresa Collins (1), Humaira Naseer (1), Brian Middleton (2), Amanda Wilson (1), Jane Stewart (1), Jerome Mettetal (3).
(1) Translational Safety, AstraZeneca, Alderley Park, UK, (3) Statistics, AstraZeneca, Alderley Park, UK, (3) Translational Safety, AstraZeneca, Waltham, USA.
Objectives: In rodent studies, microsampling offers opportunity to sample main study animals for toxicokinetic (TK) assessment rather than satellite animals. This work compares various potential microsampling regimes proposed for main study animal sampling to explore which had the lowest bias and the influence of greater inter-animal variability on outcome of the TK parameter estimation was assessed.
Methods: Concentration data from a single compound, single dose, from 3 animals serially bled over 6 time-points was used as a basis for simulations (oral 1 compartment PK model). Several sampling designs were simulated including composite, serial approaches [1] and richly sampled, the latter was assumed to be true value for bias calculations for the other designs. Inter-animal variability on parameter estimates was varied by 10%, 30% and 50%. Using stochastic simulation and estimation, 1000 sample studies were simulated for each design using parameters estimated from a measured TK satellite group.
Results: Overall the sampling designs performed similarly under low inter-individual variability in terms of bias on PK parameter estimates (clearance, volume, Cmax, AUC). With increased inter-animal variability performance declined for all designs.
Conclusions: Rather than using a satellite group, we show that a reasonable TK assessment can be estimated by using microsampling within main study animals, and may provide greater insight in the development of exposure-response relationships. Additionally this work provides a 3Rs (reduction, refinement, replacement) benefit through the use of simulations as a replacement for an investigative study as well as reducing the need for satellite groups in future toxicological studies.
References:
[1] Sparrow, S.S.; Robinson, S.; Bolam, S.; Bruce, C.; Danks, A.; Everett, D.; Fulcher, S.; Hill, R.E.; Palmer, H.; Scott, E.W. and Chapman, K.L.. Opportunities to minimize animal use in pharmaceutical regulatory general toxicology: A cross-company review. Regulatory Toxicology and Pharmacology. 61 (2011) 222-229.
Reference: PAGE 23 (2014) Abstr 3174 [www.page-meeting.org/?abstract=3174]
Poster: Methodology - Study Design