Comparative Effects of Paclitaxel and Docetaxel on the Metabolism and Pharmacokinetics of Epirubicin in Breast Cancer Patients

Esposito, Mauro; Venturini, M.; Vannozzi, Maria Ornella; Tolino, G.; Lunardi, Gianluigi; Garrone, Ornella; Angiolini, Catia; Viale, Maurizio; Bergaglio, M.; Mastro, Lucia Del; Rosso, Riccardo

doi:10.1200/jco.1999.17.4.1132

Cited by 64 publications

(33 citation statements)

References 23 publications

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“…While no change in the pharmacokinetic profile of epirubicin was observed when followed by either paclitaxel or docetaxel, there were clear differences between the effects that each taxane had on the epirubicin metabolites. Statistically significant increases in C max (78.5 ng/ml versus 61.9 ng/ml, p < 0.05) and AUC (1,521 ng/ml/hour versus 848 ng/ml/hour, p < 0.01) of epirubicinol (EOL) were observed when epirubicin was followed by paclitaxel but not when it was followed by docetaxel [25]. These data indicate that there is no apparent pharmacokinetic interaction between the taxanes and the parent compound, epirubicin, whereas the epirubicin metabolite EOL is clearly more affected by paclitaxel than docetaxel.…”

Section: Drug Interactionsmentioning

confidence: 98%

Preclinical Pharmacology of the Taxanes: Implications of the Differences

2004

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Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to β β-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. Docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition, docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux. Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio-and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons. The Oncologist 2004;9(suppl 2):3-8 The Oncologist 2004;9(suppl 2):3-8 www.TheOncologist.com

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Section: Drug Interactionsmentioning

confidence: 98%

Preclinical Pharmacology of the Taxanes: Implications of the Differences

2004

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“…Therefore, pharmacokinetic studies of cancer patients sought to establish whether the higher than expected cardiotoxicity of some anthracycline-taxane combinations could be caused by anomalous increases of secondary alcohol metabolites in plasma. Paclitaxel reduced the systemic elimination of doxorubicinol and increased its plasma levels during the course of doxorubicin-paclitaxel infusions (Gianni et al, 1997); however, paclitaxel increased also the plasma levels of epirubicinol and epirubicinol glucuronide during infusion of the less cardiotoxic paclitaxel-epirubicin combination (Esposito et al, 1999;Grasselli et al, 2001). Docetaxel did not alter doxorubicin(ol) elimination (D'Incalci et al, 1998), whereas it increased the plasma levels of epirubicinol in some studies (Rischin et al, 2002) but not in others (Esposito et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…We considered that patients treated with anthracyclines exhibit measurable levels of doxorubicinol or epirubicinol also in plasma; therefore, we characterized whether doxorubicinol and epirubicinol could diffuse from plasma into the heart. To probe such a possibility, we incubated myocardial strips in plasma added with 0.1 M doxorubicinol or epirubicinol, similar to or higher than the C max of either metabolite during the course of anthracycline-taxane infusions (Gianni et al, 1997;Esposito et al, 1999;Grasselli et al, 2001). Neither doxorubicinol nor epirubicinol diffused from plasma into the strips; only the lipophilic doxorubicinolone, also used 0.1 M, diffused from plasma and reached a myocardial level of 0.09 Ϯ 0.01 M (mainly localized to the soluble fraction).…”

Section: Tablementioning

confidence: 99%

Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

Salvatorelli¹,

Menna²,

Gianni³

et al. 2006

J Pharmacol Exp Ther

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The antitumor anthracycline doxorubicin induces a dose-related cardiotoxicity that correlates with the myocardial levels of its secondary alcohol metabolite doxorubicinol. Combining doxorubicin with taxanes such as paclitaxel or docetaxel may aggravate cardiotoxicity, presumably because the taxanes cause an allosteric-like stimulation of cytoplasmic aldehyde reductases that convert doxorubicin to doxorubicinol in the heart. A less severe aggravation of cardiotoxicity was observed on combining taxanes with epirubicin, a closely related analog of doxorubicin; therefore, we characterized whether the cardiac tolerability of epirubicin-taxane therapies could be due to a defective taxane stimulation of the conversion of epirubicin to its secondary alcohol metabolite epirubicinol. Comparisons between doxorubicin and epirubicin in isolated human heart cytosol showed that epirubicin exhibited a lower V max /K m value for reaction with aldehyde reductases and a defective stimulation of epirubicinol formation by paclitaxel or docetaxel. A similar pattern occurred in the soluble fraction of human myocardial strips incubated in plasma with anthracyclines and paclitaxel or docetaxel, formulated in their clinical vehicles Cremophor EL or polysorbate 80. Doxorubicin, but not epirubicin, was also able to generate reactive oxygen species in the membrane fraction of myocardial strips; however, the levels of doxorubicin-derived reactive oxygen species were not further augmented by paclitaxel. These results support the notion that taxanes might aggravate the cardiotoxicity of doxorubicin through a specific stimulation of doxorubicinol formation. The failure of paclitaxel or docetaxel to stimulate epirubicinol formation therefore uncovers an important determinant of the improved cardiac tolerability of epirubicin-taxane combinations.The anthracycline doxorubicin and the taxanes paclitaxel or docetaxel are highly active antitumor drugs. Doxorubicinpaclitaxel combinations were shown to induce high response rates in women with metastatic breast cancer, particularly when the two drugs were administered almost concomitantly; unfortunately, however, the clinical use of doxorubicinpaclitaxel combinations was limited by a higher than expected incidence of the cardiac toxicity known to be induced by doxorubicin. For example, doxorubicin immediately followed by paclitaxel caused congestive heart failure (CHF) at a cumulative dose of 420 to 480 mg of doxorubicin/m 2 , which was below a safety limit usually set at ϳ500 to 550 mg of doxorubicin/m 2 (Gianni et al., 1995). Paclitaxel alone had not been reported to induce CHF; therefore, the unexpected cardiotoxicity of doxorubicin-paclitaxel uncovered a cardiotoxic synergism between the anthracycline and the taxane and prompted studies that identified 360 mg of doxorubicin/m 2 as the highest cumulative dose of anthracycline, which could be safely administered in combination with paclitaxel (Perotti et al., 2003).A higher than expected incidence of cardiotoxicity was not observed in metastat...

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“…The equimolar dose ratio of doxorubicin to epirubicin for cardiotoxicity is 1:1.7-2.0 [1]. A recent meta-analysis showed no evidence of a significant difference between epirubicin and doxorubicin in the occurrence of clinical heart failure [2]; however, there is some suggestion of a lower rate of this complication in patients treated with epirubicin [3].…”

Section: Introductionmentioning

confidence: 99%

“…To highlight the preclinical dysfunction threshold that our technique was able to detect, all patients underwent a complete analysis of all variables 24 hours and 1 week after each 100 Ϯ 20 mg/m 2 epirubicin dose. We prospectively evaluated the acute (24 hours and 1 week after) and late (3,6,12, and 18 months of follow-up) effects of epirubicin administration. The follow-up started from the time of the last epirubicin administration.…”

Section: Introductionmentioning

confidence: 99%

Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

et al. 2008

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A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age ؎ standard deviation, 59 ؎ 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (

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Comparative Effects of Paclitaxel and Docetaxel on the Metabolism and Pharmacokinetics of Epirubicin in Breast Cancer Patients

Abstract: There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.

Cited by 64 publications

References 23 publications

Preclinical Pharmacology of the Taxanes: Implications of the Differences

Preclinical Pharmacology of the Taxanes: Implications of the Differences

Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

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