Effect of Repetitive Administration of Doxorubicin-Containing Liposomes on Plasma Pharmacokinetics and Drug Biodistribution in a Rat Brain Tumor Model

Abstract

The incorporation of doxorubicin in long-circulating sterically stabilized liposomes (SSL-DXR) alters the pharmacokinetics and biodistribution of doxorubicin and therefore has the potential to alter the pharmacologic properties of doxorubicin. Previously, we showed that repetitive administration of SSL-DXR alters tumor vascular permeability. Here, we investigated the effect of weekly i.v. injections of SSL-DXR on plasma pharmacokinetics and drug biodistribution in the orthotopic 9L rat brain tumor model. The pharmacokinetics of free doxorubicin (5.67 mg/kg) did not change with repeat dosing. In contrast, drug concentrations in plasma and brain tumor increased and deposition in liver and spleen decreased after administration of the second of two weekly doses of SSL-DXR. Noncompartmental analysis and descriptive pharmacokinetic models were created to test hypotheses relating to the mechanisms responsible for alterations in SSL-DXR deposition. The analysis suggested that weekly administration of SSL-DXR significantly (P < 0.05) decreased the plasma elimination rate of SSL-DXR (34%) and decreased drug deposition in liver (2-fold) and spleen (3.5-fold). The pharmacokinetic model that best captured the observed 2.5-fold increase in tumor uptake of SSL-DXR mediated by repeat dosing was one that hypothesized that the rates of drug influx/efflux into tumor were increased by the first dose of SSL-DXR. Models that accounted only for residual drug deposited in the tissue or blood by the first weekly injection provided inferior fits to the data. Thus, the effects of repetitive dosing on SSL-DXR deposition in tumor are consistent with a treatment-mediated alteration of tumor vascular permeability.