Pharmacokinetics of daunorubicin as a determinant of response in acute myeloid leukemia

Twenty-one adult patients with acute myeloid leukemia (AML) were treated with the EORTC LAM-6 remission induction protocol [daunorubicin (DNR) (45 mg/m2, days 1-3), cytarabine (200 mg/m2, days 1-7) and vincristine (1 mg/m2, day 2)]. Pharmacokinetics of DNR were studied at day 1. The concentration of DNR and daunorubicinol were determined in plasma, in white blood cells and in bone marrow. A large variability was observed with respect to (1) the plasma area under the curve (AUC) 0-24 h (range: 0.06-0.37 nmol X h/ml); (2) the white cell AUC 0-24 h (range: 0-441 nmol X h/10(9) cells); and (3) the 1 h bone marrow concentration (range: 0-27 nmol/10(9) cells). In eight patients treated twice, a small intraindividual variability of these parameters was observed. Concentrations in plasma did not correlate with cellular concentrations. All pharmacokinetic parameters in plasma and white cells did not correlate with response to therapy. In patients reaching complete remission (CR), however, the tumor load, as expressed by the number of blast cells present in the untreated bone marrow, was significantly lower than the number of blast cells in patients not reaching CR.