Pharmacokinetics and Determination of Tumor Interstitial Distribution of a Therapeutic Monoclonal Antibody Using Large-Pore Microdialysis.

Abstract

R7072 is a fully human monoclonal antibody (mAb) exerting anti-tumor activity via blockade of insulin like growth factor 1 receptor. The tumoral interstitial concentrations are anticipated to be better surrogates of active site concentrations than commonly used serum concentrations for pharmacokinetic-pharmacodynamic correlation of anti-tumor mAbs. Previously, a large-pore microdialysis technique for measuring tissue interstitial concentrations of R7072 in non-tumor bearing mice was established. In the current studies, the serum pharmacokinetics of R7072 were assessed and tissue interstitial concentrations were measured by large-pore microdialysis following intravenous and intraperitoneal administration of R7072 in tumor bearing mice. R7072 exhibited nonlinear pharmacokinetics in the studied dose range. Tumor and subcutaneous interstitial concentration data suggested some delay in tissue distribution after dosing. A dose-dependent increase in the ratio of tumor interstitial to serum concentration was observed indicating target-mediated drug disposition in tumor tissue. However, subcutaneous interstitial to serum concentration ratios were similar across the doses as observed previously in non-tumor bearing mice. A two-compartment population pharmacokinetic model with subcutaneous and tumor as open-loop compartments comprising of parallel linear and non-linear elimination from serum, linear disposition from subcutaneous interstitium and non-linear disposition from tumor interstitium was developed to simultaneously describe the pharmacokinetic data from all matrices.