Investigations into the route of uptake and pharmacokinetics of intraperitoneally administered murine monoclonal antibodies for the treatment of cancer.

Abstract

The kinetic behavior of intraperitoneally (ip) administered proteins is poorly understood. As the administration of radiolabeled monoclonal antibodies becomes more commonplace for the diagnosis of ovarian cancer and considering the potential toxic effect of therapeutic doses of these compounds, the need to accurately describe the pharmacokinetics of these entities is vital. Time course experiments which track the quantity of iodine-labeled 5G6.4 (a murine IgG2a$\kappa$) in the blood, peritoneal fluid, urine, and selected tissues in the rat were designed to examine the effectiveness of the intraperitoneal route as an alternative to systemic administration, the effect of antibody class, tumor burden, and dosing variables on the pharmacokinetics of ip-administered monoclonals, and the nature of peritoneal transport as it pertains to these high molecular weight species. These studies indicate that the peritoneal cavity offers a distinct advantage to systemic administration, prolonging the length of time that the radiolabeled monoclonal bathes the tumored site and increasing overall tumor uptake. There is no difference in the amount of time that various antibody classes stay in the peritoneal cavity despite molecular weights ranging from 50,000 to 90,000 D. The presence of intraperitoneal tumors slows down the clearance of antibody from the cavity as indicated by absorption rate constants which are 8 times smaller in tumor-involved mice. Scarification of the terminal lymphatics qualifies the role of the lymphatics in peritoneal absorption. Blockade of the diaphragmatic lymphatics decreases the rate of systemic appearance, but blood levels and histologic examination reveal that the parasternal lymphatics responsible for the bulk of lymphatic uptake are unaffected. The qualitative pattern of fluid absorption is similar for all protein concentrations, however the rate of peritoneal clearance of $\sp{125}$I-5G6.4 is dependent upon intraperitoneal concentration and lymphatic flow. Large injection volumes increase diuresis and subsequently decrease the amount of free iodine liberated from the antibody. Finally, equilibrium distribution ratios and organ blood flows/organ volumes can be predicted from coefficients and exponents of fitted tissue and blood data after ip-administration of $\sp{125}$I-5G6.4 indicating that ip-administration of radiolabeled monoclonals enters peripheral tissues from the systemic circulation in a homogeneous manner.