Modification of doxorubicin-induced cardiotoxicity: manipulation of the dosage schedule

Abstract

Modification of the dosing schedule for doxorubicin (DOX) administration represents a possible method of reducing cardiotoxicity from this potent anti-cancer drug, while at the same time maintaining its cytotoxic action. The quantitative effects of modified dosage scheduling have been investigated in a clinically relevant rat model. Cardiotoxicity to DOX was assessed by the degree of reduction in cardiac output at 4-24 weeks after the intravenous administration of DOX. The effects of dose schedules involving three or six small dose administrations, over one and two weeks, were compared with that produced by large single doses of DOX. The total drug dose administered for each schedule was varied in order to establish dose-effect relationships. After a total dose of 3 mg/kg DOX, given as three or six equal small doses, there was a gradual decline in cardiac output in the first 12 weeks after drug administration. Between 12 and 24 weeks, the reduction in cardiac function was relatively stable at between 65% and 85% of that of age-matched controls for three and six equal small doses, respectively. Dose-effect curves for animals showing a > or = 30% reduction in cardiac function after 12 weeks indicated the degree of reduction in cardiac function produced by the modified dose scheduling. Compared with a large single dose, larger total doses were required to produce the same severity of damage. Thus, schedules based on three and six equal small doses resulted in dose modification factor of 1.5 +/- 0.23 and 2.1 +/- 0.28, respectively, when compared with the same effect produced by a large single dose. This appeared to be independent of the severity of cardiac damage, suggesting a simple mathematical relationship between the total acceptable dose of DOX and the dose administered at each intravenous injection. These modifications in the cardiotoxicity of DOX produced by the administration of multiple small doses were of the same order of magnitude as that produced by other methods introduced to reduce anthracycline cardiotoxicity.