Evidence of possible dose-dependent doxorubicin plasma kinetics in man

The published plasma clearance profiles of doxorubicin in man (with differing liver status) have been analyzed further using a kinetic model instead of a linear regression model. At high (60 mg/m2 and 45 mg/m2) and intermediate (30 mg/m2) doxorubicin dose levels, a triphasic drug clearance pattern is apparent. However, at a low dose level (15 mg/m2), a biphasic profile can adequately describe the kinetics. This association of the kinetics with drug dose has been demonstrated in several ways, the simplest of which involves graphic overlaying of juxtaposed plasma clearances, and shows the emergence of a kinetic profile for low dose levels that is markedly different from that at high dose levels. At doses greater than about 45 mg/m2, a probable saturation of response mechanisms is observed. It is not possible to interpret these results in terms of pure dose-dependent responses because of the varying health status of the individual subjects between and within experimental treatment. However, in light of our findings further investigation into the possibility of such an effect should be undertaken, particularly in view of its clinical ramifications.