Pharmacokinetic modeling of radiolabeled antibody distribution in man.
This paper describes a method for the interpretation of the pharmacokinetics in cancer patients of an anti-CEA monoclonal antibody labeled with 111In. To determine the fate of the radiolabeled antibody administered i.v. to ten colon patients, the radioactivity contained in liver, spleen, kidneys, bone marrow, and tumor was measured and serum samples were counted. In addition each serum and urine sample was also analyzed by HPLC. The labeled antibody and two other radioactive species were observed in serum: an immunocomplex and a catabolic product. The computer program SAAM was used to fit the data. Thus, the rate constants for a number of pharmacokinetic models were calculated using the time-dependent serum radioactivity curves for each of the three species and the time-dependent radioactivity contained in normal organs. We also computed the model parameters for different connections between different organs, and using noncompartmental methods, the transit time, permanence time, and yield of those organs. Our results suggest that the immunocomplexes are formed in the circulation between circulating antibody and antigen, and that the rate of uptake by the liver depends on the concentration of the antibody in blood and not of the immunocomplex. Following deposition in the liver, free antibody does not appear to reenter the circulation, but once there it is catabolized. All breakdown products are then cleared into urine via serum.
Rescigno
A
A
School of Pharmacy, University of Parma, Italy.
Bushe
H
H
Brill
A B
AB
Rusckowski
M
M
Griffin
T W
TW
Hnatowich
D J
DJ
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging*; D006801:Humans; D007205:Indium Radioisotopes; D008956:Models, Chemical; D011877:Radionuclide Imaging; D012984:Software; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007205:Indium Radioisotopes