Pharmacology study of chronic oral idarubicin for breast cancer

Toffoli, Giuseppe; Sorio, Roberto; Aita, P.; Crivellari, Diana; Corona, Giuseppe; Bearz, Alessandra; Robieux, I.; Colussi, A.M.; Boiocchi, Mauro; Veronesi, Andrea

doi:10.1016/s0959-8049(99)81591-3

Cited by 10 publications

(21 citation statements)

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“…(Binaschi et al (2001)]. In addition, IDA may be administered orally [with ϳ10 to 30% bioavailability (Toffoli et al, 2000)], and in vitro studies have indicated that it might be more effective than DNR in tumor cell lines displaying the multidrug resistance (MDR) phenotype (Toffoli et al, 1994;Jonsson-Videsater et al, 2003). There is some controversy about whether IDA offers advantages over DOX or DNR also in regard to cardiac toxicity.…”

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confidence: 99%

“…There is some controversy about whether IDA offers advantages over DOX or DNR also in regard to cardiac toxicity. Some authors conclude that oral IDA does not induce cardiotoxicity (Borchmann et al, 1997;Lipp and Bokemeyer, 1999;Toffoli et al, 2000), not even in patients previously exposed to DOX or EPI (Toffoli et al, 1997); in contrast, others have shown that IDA decreases left ventricular ejection fraction (LVEF) in anthracycline-naïve patients, and causes CHF in patients with pre-existing cardiovascular disease or previous anthracycline treatment (Anderlini et al, 1995). Thus, the cardiac safety of IDA awaits further assessment in patients properly randomized in terms of cumulative dose and individual risk factors.…”

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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“…12 We therefore designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa and melphalan (HD-TM) with autologous stem cell support in metastatic breast cancer patients with stable disease or in partial response after six courses of induction GET. End points of the study were: (1) to determine the maximum tolerated dose (MTD) of idarubicin with peripheral blood progenitor cells, (2) to determine the cardiac safety of HD-Ida followed by double high-dose alkylators, (3) to evaluate the activity of HD-Ida after GET, (4) to study the pharmacokinetic profile of idarubicin on plasma and cerebrospinal fluid (CSF).…”

Section: Static Breast Cancermentioning

confidence: 99%

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

Bengala¹,

Danesi²,

Guarneri³

et al. 2003

Bone Marrow Transplant

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Summary: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 7.772.0 and 26.379.7 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 423.27111.6 and 25817606 hng/ml at 40 mg/m 2 to 732.87140.2 and 459071258 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 crossresistance between the two drugs. High-dose chemotherapy (HDC) with autologous hemopoietic support has been used as intensification/consolidation treatment in advanced breast cancer responsive to standard chemotherapy. However, despite encouraging preclinical data and phase II results, preliminary data from phase III randomized trials have failed to show any survival benefit. 1-4 Most of the randomized trials have used four to six courses of induction chemotherapy followed by late intensification with a single course of HDC. High-dose regimens usually have included alkylating agents because of their steep dose-response curve, non-cell cycle specificity and broad clinical activity. 5 Attempts to improve these disappointing results include the development of more active induction regimens, the upfront use of HDC and sequential administration of high-dose drugs or regimens.Our group has shown that the combination of gemcitabine+epirubicin+paclitaxel (GET) is very active with an overall response rate of 92% and a complete response rate of 31%; 6 the administration of high-dose thiotepa followed by high-dose melphalan as consolidation of GET induces an improvement in quality of response in 44% of patients. 7 On the basis of the promising activity and acceptable toxicity observed in this study...

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“…The present study further supports the utility of pharmacokinetic modeling in identifying sites of drug interactions within the heart. Idarubicin (IDA 1 ) and related anthracycline antibiotics are among the most powerful anticancer drugs (e.g., Weiss, 1992;Toffoli et al, 2000). However, the irreversible cardiotoxicity of anthracyclines limits their therapeutic use (e.g., Keefe, 2001).…”

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Modeling the Metabolism of Idarubicin to Idarubicinol in Rat Heart: Effect of Rutin and Phenobarbital

Kang¹,

Weiß²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Since the severe cardiotoxicity of anthracyclines has been attributed to the intramyocardial formation of C-13 alcohol metabolites, the kinetics of cardiac metabolite formation and disposition as well as the effect of carbonyl reductase inhibitors are of specific interest. This study was designed to investigate the effect of rutin and phenobarbital on the pharmacokinetics of idarubicin (IDA) and its conversion to idarubicinol (IDOL) in the single-pass perfused rat heart. After infusion of IDA (0.5 mg) during 1min, the venous outflow concentrations of IDA and IDOL were measured up to 80 min in the presence and absence of rutin and phenobarbital. A kinetic model was developed to help to interpret the concentration profiles in terms of compartmentation of IDOL formation and to estimate parameters quantitatively descriptive of the transport and biotransformation processes. Rutin and phenobarbital significantly reduced the residual amount of IDOL in heart to 64 and 47% of control, respectively. Pharmacokinetic modeling of the data revealed that IDOL is generated in two different compartments, besides the tissue compartment characterized by saturable uptake, also the compartment that accounts for the quasi-instantaneous initial distribution process is involved. The efflux rate constant of IDOL, k 21,IDOL, was much smaller than that of IDA. Rutin and phenobarbital significantly reduced IDOL production. Additionally, phenobarbital competitively inhibited the saturable uptake of both IDA and IDOL (increase in apparent Michaelis constants). Reanalysis of data obtained in previous experiments showed that Pglycoprotein inhibitors (verapamil and amiodarone) reduced IDOL uptake in a similar way as already shown for IDA. The present study further supports the utility of pharmacokinetic modeling in identifying sites of drug interactions within the heart.

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Pharmacology study of chronic oral idarubicin for breast cancer

Cited by 10 publications

References 0 publications

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

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

Modeling the Metabolism of Idarubicin to Idarubicinol in Rat Heart: Effect of Rutin and Phenobarbital

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