Pharmacokinetic modeling for evaluating dosing strategies of anti-p185HER2 monoclonal antibodies

Pharmacokinetic modeling can be a valuable tool In the development of potential therapeutics. To Illustrate its use In evaluating dosing regimens, an example with monoclonal antibodies (MAb) directed against the extracellular domain of the protooncogene product (p185^HER2) is presented. Preclinical studies have shown that these MAb have an antiproliferative effect on tumors that overexpress P185^HER2. Intact antibodies (4D5, HER2) or an antibody fragment (4D5 F(ab´)2) were administered to female CD1 mice either Intravenously (IV) or intraperltoneally (IP), and single serum samples at scheduled times were collected after injection. Antibody concentrations were measured by ELISA. Serum time-course data were fitted to compartmental models, and model parameters were subsequently used to simulate serum antibody concentrations by Introducing multiple inputs to the central compartment. The 4D5 F(ab´)2 cleared from the circulation much more rapidly (≈15 times) than the intact antibodies; therefore, the dosing schedule for 4D5 F(ab´)2 would be different from Intact antibodies If the same target concentration Is to be achieved. In this study, the route of administration, IV or IP, did not greatly alter the systemic exposure of the molecule because IP absorption was relatively rapid and nearly complete.