The effect of age on the early disposition of doxorubicin

PURPOSE: Clinical studies indicate that anthracycline cardiotoxicity increases with patient age. This may be due to altered pharmacokinetics or pharmacodynamics. A parameter termed 'early clearance' has been shown to decrease with age in patients receiving intravenous doxorubicin. This parameter, as defined, has no immediate relationship to any physiologically based pharmacokinetic parameter. We therefore reevaluated the pharmacokinetic data to better define the relationship between doxorubicin disposition and patient age. METHODS: Four studies provided a total of 56 patients with evaluable pharmacokinetics. The volume of the central compartment, V(c), the distribution clearance, CL(d), and total body clearance, CL, were determined for each patient and regressed against age. A physiologically based pharmacokinetic (PBPK) model for doxorubicin was also used to evaluate the effects of age on doxorubicin disposition. Published blood flows associated with various patient ages were used to simulate plasma and tissue doxorubicin concentrations. The relationship between CL(d) and initial tumor regression was also evaluated. RESULTS: No correlation was found between V(c) and age ( P>0.05). A highly significant correlation was observed between CL(d) and age ( P<0.0005) and there was a mild but significant relationship between CL and age ( P<0.01). Use of the PBPK model with different age-related blood flows yielded virtually identical parameter values to the clinical data analyzed. Furthermore, relative tissue AUCs simulated in old and young patients compared well with those reported for daunorubicin disposition in young and old rats. In addition, a linear relationship was observed between initial tumor regression and CL(d). CONCLUSIONS: Initial concentrations of doxorubicin following intravenous administration are higher in the elderly due to a decrease in CL(d) rather than in V(c). On the basis of simulations with the PBPK model, the reduced CL(d) appears to be related to altered regional blood flows in the elderly, and such changes may be of clinical significance.