Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia

Liposomal formulations of anthracyclines have been developed to increase th eir delivery to solid tumors while reducing toxicity in normal tissues. Dau noXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubic in registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokineti cs in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m(2) IV on days 1, 3, and 5. Blood and urine samples were collected at appropri ate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunoru bicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t (1/2 alpha) 4.54 +/- 0.87 h; Vd(ss) 2.88 +/- 0.93 l/m(2); Cl 0.47 +/- 0.26 l/h/m(2)) showed that in patients with acute leukemia liposomal-entrapped d aunorubicin pharmacokinetics greatly differed from that observed for the co nventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC(0-infinity) 456.27 +/- 182.64 mu g/ml/h) about 100- to 200-fold greate r than those reported for the free drug at comparable doses due to a very m uch lower total body clearance. Volume of distribution at steady state was 200- to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 /- 7.13 mu g/ml . h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showe d that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicit y was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorub icin captation in normal tissues, thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bl oodstream and bone marrow, thus theoretically improving efficacy.