Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration

Purpose: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. Methods: Doxorubicin 0.5-9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNON-LIN 4.2. Results: Concentration-time data were best described in all pigs by a two- compartment open model of elimination. Independent of the route of administration, AUC and C(max) values increased with dose. Mean systemic AUC and C(max) values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. Conclusions: Administration of doxorubicin by HAI with simultaneous HVDE significantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses.