Development and Evaluation of a Novel Method for Preclinical Measurement of Tissue Vascular Volume

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• 作者：C. Andrew Boswell ; Gregory Z. Ferl ; Eduardo E. Mundo ; Michelle G. Schweiger ; Jan Marik ; Michael P. Reich ; Frank-Peter Theil ; Paul J. Fielder ; Leslie A. Khawli
• 刊名：Molecular Pharmaceutics
• 出版年：2010
• 出版时间：October 4, 2010
• 年：2010
• 卷：7
• 期：5
• 页码：1848-1857
• 全文大小：274K
• 年卷期：v.7,no.5(October 4, 2010)
• ISSN：1543-8392

文摘

Identification of clinically predictive models of disposition kinetics for antibody therapeutics is an ongoing pursuit in drug development. To encourage translation of drug candidates from early research to clinical trials, clinical diagnostic agents may be used to characterize antibody disposition in physiologically relevant preclinical models. TechneScan PYP was employed to measure tissue vascular volumes (V_v) in healthy mice. Two methods of red blood cell (RBC) labeling were compared: a direct in vivo method that is analogous to a clinical blood pool imaging protocol, and an indirect method in which radiolabeled blood was transfused from donor mice into recipient mice. The indirect method gave higher precision in RBC labeling yields, lower V_v values in most tissues, and lower ^99mTc uptake in kidneys and bladder by single photon emission computed tomographic (SPECT) imaging relative to the direct method. Furthermore, the relative influence of each method on the calculated area under the first 7 days of the concentration−time curve (AUC₀₋₇) of an IgG in nude mice was assessed using a physiologically based pharmacokinetic model. The model was sensitive to the source of V_v values, whether obtained from the literature or measured by either method, when used to predict experimental AUC₀₋₇ values for radiolabeled trastuzumab in healthy murine tissues. In summary, a novel indirect method for preclinical determination of V_v offered higher precision in RBC labeling efficiency and lower renal uptake of ^99mTc than the direct method. In addition, these observations emphasize the importance of obtaining accurate physiological parameter values for modeling antibody uptake.

Keywords:

Vascular volume; red blood cell labeling; TechneScan PYP; physiologically based pharmacokinetic modeling