PHARMACOKINETIC ANALYSIS OF THE MICROSCOPIC DISTRIBUTION OF ENZYME-CONJUGATED ANTIBODIES AND PRODRUGS - COMPARISON WITH EXPERIMENTAL-DATA

A mathematical model was developed to improve understanding of the bio distribution and microscopic profiles of drugs and prodrugs in a syste m using enzyme-conjugated antibodies as part of a two-step method for cancer treatment. The use of monoclonal antibodies alone may lead to h eterogeneous uptake within tumour tissue; the use of a second, low mol ecular weight agent may provide greater penetration into tumour tissue . This mathematical model was used to describe concentration profiles surrounding individual blood vessels within a tumour. From these profi les the area under the curve and specificity ratios were determined. B y integrating these results spatially, average tissue concentrations w ere determined and compared with experimental results from three diffe rent systems in the literature: two using murine antibodies and one us ing humanised fusion proteins. The maximum enzyme conversion rate (V-m ax) and the residual antibody concentration in the plasma and normal t issue were seen to be key determinants of drug concentration and drug- prodrug ratios in the tumour and other organs. Thus, longer time delay s between the two injections, clearing the antibody from the bloodstre am and the use of 'weaker' enzymes (lower V-max) will be important fac tors in improving this prodrug approach. Of these, the model found the effective clearance of antibody outside of the tumour to be the most effective. The use of enzyme-conjugated antibodies may offer the follo wing advantages over the bifunctional antibody-hapten system: (i) more uniform distribution of the active agent; (ii) higher concentrations possible for the active agent; and (iii) greater specificity (therapeu tic index).