Phase I trial with 4′-deoxydoxorubicin (esorubicin)

Rozencweig, Marcel; Crespeigne, N.; Kenis, Yvon

doi:10.1007/bf00177414

Cited by 21 publications

(7 citation statements)

References 7 publications

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“…The weekly administration schedule appeared, in addition, particularly promising on the basis of the apparent schedule dependency of the antitumor activity observed in some experimental models (2). In agreement with the data of the single dose intermittent schedule (7)(8)(9), this Phase I trial shows that leukopenia is the major dose-limiting toxic effect of 4'-deoxydoxorubicin, with thrombocytopenia almost exclusively occurring in patients with a WBC < 1500//d. The narrow ranges of values and times of nadirs reported in this study confirm the previous suggestion of a well predictable hematologic toxicity, with prior chemotherapy and performance status as important factors affecting the hematologic tolerance.…”

Section: Discussionsupporting

confidence: 67%

Phase I trial of 4′-deoxydoxorubicin given weekly

Sessa¹,

Bosia²,

Kaplan³

et al. 1984

Invest New Drugs

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Twenty-six patients with various solid tumors entered a Phase I trial with 4'-Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3-4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m2 weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m2 can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted.

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Section: Discussionsupporting

confidence: 67%

Phase I trial of 4′-deoxydoxorubicin given weekly

Sessa¹,

Bosia²,

Kaplan³

et al. 1984

Invest New Drugs

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“…In accordance to experimental findings, the clinical potency of esorubicin was approximately twice that of the parent compound (7,8,11). For single administrations every 3-4 weeks, dosages of 25-35 mg/m ~ were recommended (7,8,11). Phase II trials are ongoing in a variety of tumor types.…”

Section: Introductionmentioning

confidence: 77%

“…Myelosuppression was the dose-limiting toxicity associated with esorubicin therapy (7). We attempted to correlate various pharmacokinetic parameters versus nadirs and maximum variations (difference between the pretreatment and nadir counts) of the white blood cell, polyneutrophil, and platelet counts.…”

Section: Correlation Between Pharmacokinetic Parameters and Clinical mentioning

confidence: 99%

“…Phase I studies revealed that myelosuppression was doselimiting (7)(8)(9)(10)(11). Acute non-hematologic toxic effects were well tolerated.…”

Section: Introductionmentioning

confidence: 98%

“…* This work was presented in part at the 4th NCI EORTC Symposium on New Drugs in Cancer Therapy (Brussels, Belgium, December [14][15][16][17]1983) and at the 20th Annual Meeting of the American Society of Clinical Oncology (Toronto, Canada, May [6][7][8]1984 Doxorubicin is an anthracycline antibiotic with a wide spectrum of antitumor activity (1). Its use is limited by a number of toxic effects especially doserelated cardiomyopathy that may result in congestive heart failure with chronic drug administration (2).…”

Section: Introductionmentioning

confidence: 99%

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Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

et al. 1985

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The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40 mg/m2. All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 +/- 0.57 microM (mean +/- SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 +/- 7.3 hr. The area under the plasma concentration versus time curve was 0.64 +/- 0.31 microM x hr. Total body plasma clearance was 45.5 +/- 26.8 liter/min/m2 and the apparent volume of the central compartment, 41.0 +/- 24.8 L. A single metabolite, 4'-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 +/- 0.017 microM. The area under the plasma versus concentration time curve for 4'-deoxydoxorubicinol was 0.02 +/- 0.014 microM xhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 +/- 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4'-deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.

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Phase I and II Agents in Cancer Therapy: I. Anthracyclines and Related Compounds

Wadler

Fuks

Wiernik

1986

The Journal of Clinical Pharma

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Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.

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Phase I trial with 4′-deoxydoxorubicin (esorubicin)

Cited by 21 publications

References 7 publications

Phase I trial of 4′-deoxydoxorubicin given weekly

Phase I trial of 4′-deoxydoxorubicin given weekly

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

Phase I and II Agents in Cancer Therapy: I. Anthracyclines and Related Compounds

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