Pharmacokinetics of liposomal daunorubicin [DaunoXome] during a phase I-II study in children with relapsed acute lymphoblastic leukaemia

Purpose: The pharmacokinetics of DaunoXome were studied during a multicentric phase I-II study performed in children suffering from relapsed acute lymphoblastic leukaemia and treated on a weekly schedule. Patients and methods: A group of 18 patients were studied during the first course of treatment at dose levels between 40 and 120 mg/m(2). Blood samples were obtained up to 72 h after infusion. The liposomal and free forms of daunorubicin, as well as daunorubicinol, were separated and quantified by HPLC using fluorometric detection, and data were analysed using a model-independent approach. Results: Unchanged liposomal daunorubicin disappeared from plasma following a monoexponential decay. Its AUC represented 95.8% of the total fluorescent species found in plasma and increased linearly with the dose administered. The elimination half-life was 5.23 h, total plasma clearance 0.344 1/h per m(2), and volume of distribution at steady state 2.08 1/m(2). Free daunorubicin and daunorubicinol were detected in plasma at all time-points studied. Their AUCs represented, respectively, 2.53% and 1.70% of total fluorescent species and their elimination half-lives were, respectively, 16.6 h and 22.3 h. The daunorubicinol/daunorubicin AUC ratio was 0.82%. Conclusions: This study is the first to demonstrate that free daunorubicin is present in plasma after DaunoXome administration and that it originates from in vivo release from the liposomes. The pharmacokinetics of free daunorubicin appeared to be comparable to those observed after conventional administration. However, the concentration of daunorubicinol appeared to be lower than that found after conventional administration of daunorubicin.