Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice.
A physiologically based pharmacokinetic model to describe the biodistribution of a specific monoclonal antibody IgG1 (ZCE025) and its fragments (F(ab')2 and Fab) and of a nonspecific IgG1 (MOPC21) in normal tissues and a human colon carcinoma xenograft (T380) in nude mice is developed. The model simulates the experimental data on the concentration of these four macromolecules in plasma, urine, heart, lung, liver, kidney, spleen, bone, muscle, skin, GI tract, and tumor. This is the first such model for macromolecules with specific binding. A two-pore formalism for transcapillary solute exchange is used which avoids the oversimplifications of unidirectional transport or a single effective permeability coefficient. Comparison of the model with our biodistribution data shows that: (a) a physiologically based pharmacokinetic model for specific and nonspecific antibodies is able to explain experimental data using as few adjustable parameters as possible; (b) for antibodies and fragments, the tumor itself has no significant influence on the pharmacokinetics in normal tissues; and (c) the two-pore formalism for transcapillary exchange describes the data better than a single-pore model without introducing extra adjustable parameters. Sensitivity analysis shows that the lymph flow rate and transvascular fluid recirculation rate are important parameters for the uptake of antibodies, while for the retention of specific antibodies, extravascular binding is the key parameter. A single-pore model could also obtain a good fit between model and data by adjusting two parameters; however, the estimated permeability was 1000 times higher than with the two-pore model, and the binding affinity was such that approximately five times more material was bound than free in the extravascular space for nonspecific antibody. Setting the binding affinity to zero or reducing the value of the permeability-surface area product did not allow a good fit, even when the lymph flow rate was varied. The present model may be useful in scaling up antibody pharmacokinetics from mouse to man.
Baxter
L T
LT
Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston 02114.
Zhu
H
H
Mackensen
D G
DG
Jain
R K
RK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000918:Antibody Specificity; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D008432:Mathematical Computing; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010599:Pharmacokinetics; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G