Pharmacokinetics of weekly low dose doxorubicin

Weekly low dose doxorubicin (WLD-dox) is an interesting alternative to the classical 3 week schedule because of its reduced cardiotoxicity, the major dose-related side-effect. This study characterized the pharmacokinetic behaviour of WLD-dox with particular attention to the effect of treatment duration on the variability of individual pharmacokinetic parameters. Twenty-eight patients with advanced breast cancer were treated by WLD-dox (12 mg/m2 week). Individual pharmacokinetic analyses were performed at the first injection and every month thereafter; residual drug levels were measured every week before injection. Dox and its main metabolite doxol were measured by HPLC and fluorescence. Pharmacokinetic data were available for 51 cycles. The mean concentration-time profile for 25 patients with normal liver function tests fitted well with a two-compartment model: COext (nM) = 2905 +/- 1834; t 1/2 alpha = 0.08 +/- 0.03 h; t 1/2 beta = 10.4 +/- 3.6 h; clearance (1/h) = 55.4 +/- 24.8; Vd (1) = 809 +/- 434. The findings concur with those for classical 3-week dox schedule (45 mg/m2) analysed in six patients as controls. Exceptions were the initial extrapolated concentration and area under curves which were reduced for WLD-dox according to the dose. Dox and/or doxol overexposure was patent in all three patients with elevated pre-treatment serum bilirubin. During treatment, up to 48 WLD-dox administrations, no significant trends were noted for 10 patients in the evolution of initial extrapolated concentration, terminal half-life, total body clearance or the proportion of doxol formed. Residual drug levels were controlled up to 40 WLD-dox administrations (135 samples); in half the cases they comprised between 1 and 20 nM without particular sign of increasing along the treatment course. In this case WLD-dox can be assimilated to a continuous exposure to low drug levels with intermittent pulses thus representing an original pharmacological profile for dox.