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 biodistr ibution of a specific monoclonal antibody IgG1 (ZCE025) and its fragme nts (F(ab')(2) and Fab) and of a nonspecific IgG1 (MOPC21) in normal t issues and a human colon carcinoma xenograft (T380) in nude mice is de veloped. The model simulates the experimental data on the concentratio n of these four macromolecules in plasma, urine, heart, lung, liver, k idney, spleen, bone, muscle, skin, GI tract, and tumor. This is the fi rst such model for macromolecules with specific binding. A two-pore fo rmalism for transcapillary solute exchange is used which avoids the ov ersimplifications of unidirectional transport or a single effective pe rmeability coefficient. Comparison of the model with our biodistributi on data shows that: (a) a physiologically based pharmacokinetic model for specific and nonspecific antibodies is able to explain experimenta l data using as few adjustable parameters as possible; (b) for antibod ies and fragments, the tumor itself has no significant influence on th e pharmacokinetics in normal tissues; and (c) the two-pore formalism f or transcapillary exchange describes the data better than a single-por e model without introducing extra adjustable parameters. Sensitivity a nalysis shows that the lymph flow rate and transvascular fluid recircu lation rate are important parameters for the uptake of antibodies, whi le for the retention of specific antibodies, extravascular binding is the key parameter. A single-pore model could also obtain a good fit be tween model and data by adjusting two parameters; however, the estimat ed permeability was 1000 times higher than with the two-pore model, an d the binding affinity was such that approximately five times more mat erial was bound than free in the extravascular space for nonspecific a ntibody. 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 i n scaling up antibody pharmacokinetics from mouse to man.