High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study.

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.

Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model.

PURPOSE: Idarubicin (4-demethoxy-daunorubicin) is more potent and less cardiotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin. In addition, idarubicin is metabolized to an active metabolite, idarubicinol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhuman primates to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics of idarubicin and idarubicinol and to compare them to the pharmacokinetics of daunorubicin and daunorubicinol. METHODS: A dose of 30 mg/m2 of daunorubicin or 8 mg/m2 of idarubicin was administered intravenously over 15 minutes. Plasma and CSF were sampled frequently from the end of the infusion to 72 to 96 hours after infusion. Drug and metabolite concentrations were measured using high-pressure liquid chromatography (HPLC). RESULTS: Daunorubicin elimination from plasma was triphasic with a terminal half-life of 5.9 +/- 1.8 hours, area under the concentration-time curve (AUC) 22.5 +/- 9.2 mumol/L.min, and clearance 2790 +/- 960 mL/min/m2. Daunorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2.3 hours and an AUC 74.5 +/- 5.3 mumol/L.min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3.7 mumol/L.min, and clearance 1650 +/- 610 mL/min/m2. Idarubicinol elimination was biphasic with a terminal half-life 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mumol/L.min. CSF penetration was low for both parent drugs and their metabolites. CSF idarubicin was measurable at a single time point (1 hour after administration) for 2 animals, and was not measurable for the third. The CSF to plasma concentration ratio at that time point was 8% in 1 animal and 15% in the other. Idarubicinol was detected in 2 to 4 samples at various times, appearing as early as 1 hour in 1 animal and persisting as late as 48 hours in another. The CSF to plasma concentration ratio at corresponding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hours after intravenous administration. For individual animals, the mean CSF to plasma concentration ranged from 4% to 12%. Daunorubicinol was detectable by 1 hour in 2 of 3 animals and by 3 hours in the other, and remained detectable at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CSF was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mumol/L.min, and the AUCCSF to AUCplasma ratio was 2.4 +/- 1.9%. CONCLUSION: Idarubicin, idarubicinol, daunorubicin, and daunorubicinol penetrate poorly into the CSF after intravenous administration.

Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report.

Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.