Pharmacokinetics and lymphatic absorption of the protein VEGF-C156S
Bhansali, Surajkumar G.
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Lymphedema is a disorder of the lymphatic vascular system characterized by lymphatic insufficiency that leads to blockade of lymph flow and swelling of the extremities. VEGF-C156S is a recombinant mutant form of human vascular endothelial growth factor C (VEGF-C) that targets the receptor VEGFR-3 mainly present in the lymphatics. Owing to its lymphangiogenic properties VEGF-C156S may represent a potential therapeutic approach in treating the lymphedema. Our main objectives for this dissertation were two fold: first, to characterize the pharmacokinetics and tissue distribution of VEGF-C156S and secondly, to investigate the determinants of lymphatic uptake of proteins. The influence of route of administration and liposomal encapsulation on lymphatic uptake of VEGF-C156S was studied in mice. The overall exposure of VEGF-C156S in lymph nodes was significantly higher after the SC administration of non-liposomal or a liposomal preparation compared to IV administration. Further, the PK of VEGF-C156S after IV and SC administration was characterized in mice, demonstrating nonlinear elimination after the IV administration of a high dose. A mechanistic PK model was developed to describe the data. Target mediated drug disposition was incorporated into the model to describe the nonlinear elimination of VEGF-C156S. A ‘lymphatic’ compartment was included to characterize the lymphatic uptake of a SC-dministered dose and to characterize the distribution of protein after IV or SC administration. The modeling results indicated that 72% of SC- administered VEGF-C156S was absorbed by the lymphatics. Additionally, tissue distribution of VEGF-C156S after IV and SC administration was investigated. A physiologically based pharmacokinetic (PBPK) model was developed to characterize the blood and tissue concentrations. The disposition of VEGF-C156S in liver, kidney, spleen, heart and lung was described with perfusion being rate-limiting, whereas in gut, muscle, skin, brain, fat, testes and lymph nodes, permeability was assumed to be rate limiting. The elimination of VEGF-C156S was described as a nonlinear process. Based on studies performed using a sheep model, the lymphatics have been reported to represent the primary absorptive pathway for proteins with molecular weights (MW) greater than 16 kDa, since more than 50% of the administered dose was recovered in peripheral lymph for these proteins. We studied the effect of molecular weight on lymphatic uptake of subcutaneously administered proteins in mice. A novel noninvasive fluorescence imaging technique was developed and utilized to quantitatively measure the lymph node uptake of fluorescence-labeled proteins. The lymphatic uptake was MW dependent in the range of 23-149 kDa. In summary, this dissertation provides novel information on the PK, tissue distribution, and lymphatic exposure of the protein VEGF-C156S. Additionally, our investigations reported for the first time, the use of in vivo fluorescent imaging to determine the lymphatic uptake of proteins in a mouse model, and assessed the influence of MW of proteins on lymphatic absorption after subcutaneous administration. Key words: lymphatic uptake, subcutaneous, proteins, pharmacokinetics, modeling, quantitative imaging.