Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model.

ABSTRACT

Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.