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J Pharmacol Exp Ther. 2019 Jan 8. pii: jpet.118.252858. doi: 10.1124/jpet.118.252858. [Epub ahead of print]

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice.

Author information

1
Univeristy at Buffalo, SUNY.
2
Roswell Park Cancer Institute.
3
Univeristy at Buffalo, SUNY; dshah4@buffalo.edu.

Abstract

Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma, and have development of a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with Cr-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration, and accumulate in the tissues to various extent. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumor was found to be very low, hovering below 1 %ID/g during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T cell based therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes like extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into spleen, liver, and kidney to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provides unprecedented insight into biodistribution of exogenously administered T cells.

KEYWORDS:

cell trafficking; mathematical modeling; pharmacokinetic / pharmacodynamic modeling; pharmacokinetics

PMID:
30622170
DOI:
10.1124/jpet.118.252858
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