Abstract
Microsampling techniques enable the minimization of blood collection volume from animals and subsequent handling of the blood samples or their derived plasma or serum samples. This offers advantages over conventional large-volume sampling, such as eliminating the need for satellite animals and improving animal welfare aspects, and providing the opportunity for additional assessments in small animals where blood volume constraints limit endpoints. This study evaluated the feasibility of implementation of capillary microsampling (CMS) in a single-dose study in mice with the ultimate goal of enabling its use in toxicology studies. The focus was on the impact of microsampling on toxicokinetic assessment and on the subsequent hematology assessment in the same animal. A seventy (70)-μL blood collection via CMS from the tail vein had a minimal effect on the hematology parameters of mice (strain C57BL/6) in samples taken within 24 h of blood collection. TK parameters were similar in plasma samples collected via CMS and cardiac puncture sampling. A bioanalytical assay was developed which enabled the quantification of concentration of both the parent drug and a metabolite using only 5-μL plasma sample per analysis. Incurred sample reanalysis (ISR), unexpected event investigation, and re-assay were successfully performed on the limited samples (≤ 20 μL) collected from CMS. The results of this study confirmed the feasibility of implementing CMS in regulated mouse toxicity studies and demonstrated that it is possible to eliminate or reduce satellite animals.
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Acknowledgments
The authors would like to thank Bristol-Myers Squibb colleagues: Renee Bieniaszeski, Daniel Echevarria, Ryan Focht, Ana Garcia, Mary McManus, Rudolph Peter, and Kristy Shaulis for conducting the in life phase and formulation preparation for the study; Alban Allentoff for providing materials of BMS-817399, BMT-049560, and stable isotopic labeled internal standards and checking the purity of all compounds; Naiyu Zheng for discussion; and Megan Firestine for assistance of manuscript preparation. The authors would like to thank Michael J Graziano for his management support.
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Wang, B., Wang, L., Batog, A. et al. Investigation on the Effect of Capillary Microsampling on Hematologic and Toxicokinetic Evaluation in Regulatory Safety Studies in Mice. AAPS J 22, 55 (2020). https://doi.org/10.1208/s12248-020-00438-z
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DOI: https://doi.org/10.1208/s12248-020-00438-z