Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration

Background. Hepatic arterial infusion of doxorubicin has produced tumor response in hepatic malignancies; however, the limited success of these treatments is related in part to dose-limiting systemic toxicities. The purpose of this study was to determine whether a novel venous isolation-chemofiltration system could limit systemic exposure to doxorubicin after hepatic arterial infusion. Methods. Doxorubicin (1 or 3 mg/kg) was infused in the hepatic arteries of domestic pigs after complete hepatic venous isolation was achieved with a dual-balloon vena cava catheter. The hepatic vein effluent was pumped through an extracorporeal carbon chemofiltration circuit. Doxorubicin levels were measured in prefilter (hepatic vein), postfilter, and systemic serum at intervals up to 1 hour after drug infusion. Results. Complete hepatic venous isolation with extracorporeal chemofiltration significantly reduced (>90%) the postfilter and systemic levels of doxorubicin compared with prefilter levels (p < 0.01), At the time animals were killed 7 days after infusion of doxorubicin (3 mg/kg), tissue levels of doxorubicin in the liver showed a 16-fold increase compared- with levels in the heart (p < 0.01). Conclusions. For chemotherapeutic drugs like doxorubicin with a low first-pass extraction by the liver, the novel system described herein achieved significant reduction in systemic drug exposure. This system will allow dose intensification of doxorubicin administered by hepatic arterial infusion to treat hepatic malignancies.