This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Esposito, M. Articles by Rosso, R. Search for Related Content PubMed PubMed Citation Articles by Esposito, M. Articles by Rosso, R. Social Bookmarking                            What's this?

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

From the Pharmacotoxicology Laboratory, Department of Preclinical Oncology, and Department of Medical Oncology I, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.

Address reprint requests to Marco Venturini, MD, Divisione di Oncologia Medica I, Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi,10, 16132 Genova, Italy; email mventur{at}hp380.ist.unige.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin.

PATIENTS AND METHODS: We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m² by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m² in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m² followed immediately by docetaxel 70 mg/m² in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography.

RESULTS: No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1.7-fold and 1.9-fold higher (P < .05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 ± 150 ng/mL*h) was significantly higher (P < .01) than the corresponding values after epirubicin administered either as a single agent (692 ± 46 ng/mL*h) or in combination with docetaxel (848 ± 237 ng/mL*h).

CONCLUSION: 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE TAXANES paclitaxel and docetaxel belong to a new class of antineoplastic drugs that acts by promoting and stabilizing microtubule assembly.^1,2 These agents have already become important drugs in the management of ovarian, breast, and non–small-cell lung cancers.³ Because of their high activity as single agents in breast cancer,^4,5 a further development has been their association with anthracyclines. Studies of the combination of paclitaxel and doxorubicin have shown objective response rates ranging from 58% to 94%, which suggest high activity for this regimen.^6,7 Concerns have been raised, however, about the cardiac toxicity observed with the use of this combination. Some authors report an incidence of congestive heart failure of approximately 20%.^7,8 Limiting the cumulative doses of doxorubicin to 360 to 380 mg/m² led to a decreased incidence of congestive heart failure (approximately 5%).^7,8 However, limiting doxorubicin means that the drug can be administered only for a few cycles, and this could mean arbitrary discontinuance of an active drug in some patients who might tolerate higher cumulative doses. Epirubicin is an analog of doxorubicin with a clinical antitumor spectrum similar to that of its parent compound, but it is less cardiotoxic.⁹ Consequently, epirubicin has replaced doxorubicin in recent clinical trials.^10-12 Data from a recently published phase II study indicate that combination treatment with paclitaxel and epirubicin was quite active, with a lower incidence of cardiotoxicity than that reported with the combination of paclitaxel and doxorubicin.¹²

Docetaxel, the other taxane, has recently been reported to be the most active single agent in the treatment of advanced breast cancer patients previously exposed to alkylating agents.¹³ Because it has only recently been introduced in the clinical setting, only limited information regarding the association of docetaxel and anthracyclines is available. A study of docetaxel in combination with doxorubicin in previously untreated metastatic breast cancer patients shows promising activity associated with good tolerability.¹⁴ Moreover, results of an ongoing phase I study indicate that the association of docetaxel and epirubicin is feasible and active (73% objective response rate with no evidence of cardiac toxicity).¹⁵

Clinical pharmacologic findings have shown that paclitaxel influences the pharmacokinetic behavior of doxorubicin when delivered in both 24- and 3-hour infusions.^16,17 Generally, paclitaxel induces a higher plasma concentration of both doxorubicin and its main metabolite, doxorubicinol (DOL). By contrast, the influence of paclitaxel on the pharmacologic properties of epirubicin has not been studied as completely. Preliminary data suggest that paclitaxel does not modify the pharmacokinetics of the parent compound epirubicin, whereas it seems to significantly increase both plasma epirubicinol (EOL) exposure and epirubicin glucuronidation.¹⁸

Whereas the pharmacokinetic characteristics of docetaxel as a single agent have been extensively reported in humans,¹⁹ few preliminary data exist on the association of doxorubicin and docetaxel, and these do not evince any influence of docetaxel on doxorubicin pharmacokinetics.²⁰ No clinical data, however, are available on the possible pharmacokinetic interactions between docetaxel and epirubicin. Therefore, we sought to investigate whether differences in the pharmacokinetics and metabolism of epirubicin occur after its combination treatment with either paclitaxel or docetaxel.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was conducted at the Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. All clinical and pharmacokinetic protocols were approved by the protocol review committee and by the ethics committee of the Istituto. Informed consent was obtained from all patients before study entry.

Patient Selection
Stage II and III breast cancer patients who received epirubicin alone or a combination of epirubicin and paclitaxel as an adjuvant therapy after radical mastectomy or breast-conserving surgery were eligible for the pharmacokinetic investigations. Stage III and IV breast cancer patients who received a combination of epirubicin and docetaxel as first-line chemotherapy were also eligible. Other eligibility criteria were performance status score 1 and no other serious medical or psychiatric illness that would preclude intensive treatment and/or informed consent. All patients had to have normal bone marrow, liver, and kidney functions.

Treatment Plan and Drug Administration
Chemotherapy consisted of epirubicin alone 90 mg/m² given as an intravenous (IV) bolus; epirubicin 90 mg/m² given as an IV bolus followed immediately by paclitaxel 175 mg/m² in a 3-hour infusion; epirubicin 90 mg/m² given as an IV bolus followed by docetaxel 70 mg/m² in a 1-hour infusion. Cycles were repeated every 3 weeks. Four cycles of chemotherapy were planned for stage II patients and at least six cycles for stage III and IV patients. All patients received premedication therapy as described below.

Epirubicin, purchased as a sterile lyophilized powder in 50-mg vials, was dissolved in 25 mL of normal saline and administered intravenously over 10 minutes. Paclitaxel (Bristol-Myers Squibb SpA, Rome, Italy) was provided as a sterile solution that contained 30 mg of paclitaxel dissolved in 5 mL of polyoxyethylated castor oil (Cremophor EL [PEG35 castor oil]; BASF, Parsippany, NJ) and 50% dehydrated alcohol. The drug was diluted in 1,000 mL of normal saline to a final concentration of 0.6 mg/mL. All solutions were filtered through a 0.22-µm-pore–size cellulose acetate filter (Mirafilter IV-PVC free; Baxter, Mirandola, Italy). Paclitaxel was infused over 3 hours immediately after completion of epirubicin administration. The premedication schedule for paclitaxel consisted of 125 mg of prednisone orally at 12 and 6 hours before treatment; patients were also medicated with ranitidine 50 mg IV 30 minutes before the start of treatment and orphenadrine 40 mg intramuscularly. Rhone-Poulenc Rorer (Milan, Italy) supplied docetaxel as a sterile solution in vials containing 80 mg of docetaxel dissolved in 2 mL of polysorbate 80. Docetaxel was diluted in a 13% ethanol solution to a concentration of 10 mg/mL. The drug was diluted in 250 mL of 5% dextrose and infused over 1 hour immediately after the epirubicin injection. The premedication schedule consisted of 50 mg of prednisone orally at 12 hours, 1 hour, and immediately before docetaxel administration and ranitidine 300 mg orally the day before, the same day, and then for 2 days after docetaxel administration. All patients received granisetron 3 mg IV the day of chemotherapy as an antiemetic treatment.

Pharmacokinetic Studies
The elimination from plasma of epirubicin and its metabolites (EOL, 7-deoxydoxorubicinone [7d-Aone], and two polar metabolites sensitive to glucuronidase treatment [metabolite 1 and metabolite 2]) was investigated after a single 90-mg/m² dose of epirubicin and after the same dose of epirubicin given together with either paclitaxel or docetaxel during the first cycle of chemotherapy in all patients. Some patients underwent a second evaluation at the second cycle of chemotherapy. Heparinized venous blood samples were obtained before epirubicin administration and 5, 15, 30, and 60 minutes and 2, 3, 4, 6, 24, 48, and 72 hours thereafter. Blood samples were immediately centrifuged at room temperature, and the plasma was separated and stored in aliquots at -20°C until analysis.

Sample Analysis
Epirubicin and its metabolites in plasma were measured by high-performance liquid chromatography, using the method described by Maessen et al,²¹ with a Waters 474 scanning fluorescence detector (excitation wavelength, 480 nm; emission wavelength, 580 nm). Data were collected and analyzed using HP3365 Series II ChemStation software (Hewlett-Packard, Palo Alto, CA). Epirubicin, EOL, and 7d-Aone were identified by means of chromatographic comparison with standards. No standards were available for the two most polar peaks in the chromatogram (metabolite 1 and metabolite 2), but the incubation with beta-glucuronidase revealed that both compounds were likely to be glucuronides. These metabolites were identified in a previously analyzed plasma sample. Plasma aliquots were extracted according to the same analytic procedure used for all samples. The dried residues were dissolved in 1 mL of phosphate buffer solution (PBS; pH 6.8) with and without beta-glucuronidase (1,000 units) and incubated for 1 hour and 2 hours, respectively, at 37°C. The samples with and without beta-glucuronidase were re-extracted for chromatographic analysis. Chromatograms of the samples incubated with PBS plus beta-glucuronidase showed an incubation time-dependent decrease of the peak areas of the two most polar compounds and a proportional increase of EOL and epirubicin peak areas. No modification in peak areas was observed in the samples incubated with PBS alone. Retention times were 4.1, 5.7, 6.3, 8.3, 10.2, and 14.1 minutes for metabolite 1, metabolite 2, EOL, doxorubicin (internal standard), epirubicin, and 7d-Aone, respectively. The minimal detectable concentration was 1 ng/mL for epirubicin and its metabolites EOL and 7d-Aone.

Pharmacokinetic Calculations
Plasma epirubicin concentrations against time curves were fitted to the following multiexponential equations:

where Cp is the drug concentration at time t, A, B and C are constants, and , ß and are the apparent first-order elimination rate constants. The pharmacokinetic data were analyzed by an integrated computer system (Siphar program; Simed, Utrecht, the Netherlands) on an IBM/IC computer (IBM, White Plains, NY). The Akaike information criterion²² was used to determine which equation provided the best description of epirubicin plasma elimination. The pharmacokinetic parameters for the parent drug were calculated according to standard relationships.²³ The half-lives were calculated as:

with k = , ß, and . The area under the plasma concentration-time curve (AUC) was calculated by the linear trapezoidal rule and extrapolated to infinity (AUC_0-) by the following equation:

where C_pⁱ represents the plasma concentration at the last sampling point and k represents the elimination rate constant. Maximum peak plasma concentration was put on par with the mean concentration in the plasma samples after drug administration. The systemic clearance (CL_TB) was defined as the ratio of the delivered dose to the respective AUC value for epirubicin. The mean residence time (MRT) was calculated as the ratio of the area under the first moment curve to the AUC. The apparent volume of distribution at steady-state (V_ss) was determined by the following equation:

Values were compared with semilog approximations²³ on the basis of noncompartmental analysis (statistical moment theory) for purposes of quality control. Because of irregular C_p(t) curves, a model-independent approach was used for the metabolites EOL and 7d-Aone. The terminal half-lives of these metabolites were calculated by linear regression analysis of the logarithms of the late experimental data, and the AUCs were determined by the trapezoidal method, using data to 72 hours, and were not extrapolated. The plasma exposure (t = 0 - 72 hours) of metabolite 1 and metabolite 2 was quantitated by their total fluorescence. Analysis of pharmacokinetic data over the three patient groups was performed using one-way analysis of variance followed by a multiple comparison procedure (Newman-Keuls test). Statistical significance was determined at a level of P < .05.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Twenty-seven pharmacokinetics studies were performed on 20 female breast cancer patients. All patients had an evaluation at the first cycle, and four patients treated with epirubicin and paclitaxel and three patients treated with epirubicin and docetaxel received another evaluation at the second cycle.

No patient ever received any prior therapy for metastatic disease or prior radiotherapy and/or endocrine therapy. Two patients in the epirubicin-plus-docetaxel group had received epirubicin-based adjuvant chemotherapy; the cumulative doses of epirubicin were 300 mg/m² and 360 mg/m². All patients had a performance status score of zero. Sites of disease in four metastatic patients (epirubicin-plus-docetaxel group) were skin, skin and breast, locoregional nodes and bone, and liver and bone. Other patient characteristics are listed in Table 1.

A triexponential equation provided the best description of plasma epirubicin elimination for all patients studied. Mean plasma concentration-time curves and estimated pharmacokinetic parameters after the single 90-mg/m² dose of epirubicin and after combination treatment with either paclitaxel or docetaxel are shown in Fig 1 and Table 2. The mean ± SD systemic clearance of epirubicin when administered as a single agent was 55 ± 5.9 L/h/m². This value, the mean ± SD volume of distribution at steady-state (965 ± 221 L/m²), mean residence time (17.4 ± 6.2 hours), and mean terminal elimination half-life of epirubicin (16.3 ± 4.6 hours) were in good agreement with previous reports.^24-26 The AUC of the plasma epirubicin concentration versus time curve ranged from 1,391 to 1,961 ng/mL*h (mean ± SD, 1,588 ± 220 ng/mL*h). The administration of either paclitaxel or docetaxel did not significantly modify epirubicin pharmacokinetics (Fig 1 and Table 2). These results were comparable to those obtained from noncompartmental data analysis (data not shown).

View larger version (10K): [in this window] [in a new window]   Fig 1. Epirubicin plasma concentrations () epirubicin alone, () epirubicin plus paclitaxel, and () epirubicin plus docetaxel.

The mean plasma concentration-time curves of the metabolites EOL and 7d-Aone for each patient group are shown in Fig 2. Kinetics data are listed in Table 3. EOL appeared quickly after epirubicin administration (Fig 2A), and its terminal half-life was not significantly altered in the presence of either paclitaxel or docetaxel (18.5 ± 3.2 hours for the epirubicin alone group v 16.0 ± 0.9 or 18.9 ± 1.2 hours for the combination treatment with paclitaxel or docetaxel, respectively) and was close to that of the parent compound. In patients who received epirubicin alone and in association with docetaxel, maximum concentrations of EOL occurred within 5 minutes of the start of epirubicin administration. Plasma concentrations then decreased sharply, followed by a slower decline associated with metabolite elimination (Fig 2A). In contrast, we observed a quantitatively different metabolic rate and pattern for EOL in patients treated with epirubicin plus paclitaxel. EOL gradually increased during the 3 hours of paclitaxel infusion and peaked at a level of 78.5 ± 14.4 ng/mL at 4 hours after epirubicin injection. Moreover, the plasma levels of EOL in epirubicin-plus-paclitaxel–treated patients were significantly higher (P < .01) than those found in the epirubicin-alone and epirubicin-plus-docetaxel groups for up to 6 hours after injection (Fig 2A). Mean peak concentrations of EOL in the plasma were also higher in the epirubicin-plus-docetaxel group than in the epirubicin-alone group, but the difference was not statistically significant. Moreover, the plasma disappearance profile of EOL was similar for the epirubicin-alone and epirubicin-plus-docetaxel groups, in contrast to that of epirubicin-plus-paclitaxel–treated patients (Fig 2A). Of note, a statistically significant (P < .01) increase in EOL AUC was observed in patients who received the combination of epirubicin plus paclitaxel (1,521 ± 150 ng/mL*h), compared with the EOL AUC values for the epirubicin-alone (692 ± 46 ng/ml*h) and epirubicin-plus-docetaxel (848 ± 237 ng/mL*h) groups (Table 3).

View larger version (16K): [in this window] [in a new window]   Fig 2. Plasma concentration of (A) EOL and (B) 7d-Aone: () epirubicin alone, () epirubicin plus paclitaxel, and () epirubicin plus docetaxel.

A progressive increase in the plasma levels of 7d-Aone was observed after the concurrent administration of epirubicin with either paclitaxel or docetaxel compared with epirubicin alone (Fig 2B). In all patients, 7d-Aone levels were detectable within 5 minutes of epirubicin administration. Peak 7d-Aone levels were usually observed at 2 to 3 hours after injection of epirubicin with and without docetaxel infusion and at 6 hours after combination treatment with epirubicin and paclitaxel. Both maximum plasma levels and AUCs of 7d-Aone were nearly twice as high as epirubicin-alone values when epirubicin was given in combination with either paclitaxel or docetaxel (P < .05, Table 3). In contrast, the terminal half-life of 7d-Aone was not significantly influenced by docetaxel or paclitaxel administration (Table 3).

Peaks revealing the presence of two additional metabolites that were more polar than EOL and 7d-Aone were also detected in the plasma of all patients investigated. High-performance liquid chromatography analysis of plasma samples previously incubated with beta-glucuronidase showed that the more polar of the two (metabolite 1) was converted to a beta-glucuronidase hydrolysis product with a chromatographic identification corresponding to EOL, whereas the less polar metabolite (metabolite 2) was hydrolyzed in a product corresponding to epirubicin upon incubation with beta-glucuronidase. Based on the integrated peak area, the AUC of metabolite 1 increased 2.9-fold and 1.9-fold compared with baseline when epirubicin was given with paclitaxel and with docetaxel, respectively (Fig 3A). Similarly, 3.7-fold and 2.7-fold increases in metabolite 2 AUC were found after concurrent treatment with paclitaxel and docetaxel, respectively, compared with epirubicin alone (Fig 3B).

View larger version (17K): [in this window] [in a new window]   Fig 3. Total fluorescence of (A) metabolite 1 and (B) metabolite 2: () epirubicin alone, () epirubicin plus paclitaxel, and () epirubicin plus docetaxel.

The pharmacokinetics of epirubicin and its metabolites did not change significantly when patients receiving the same combination regimen at the first and second cycles of chemotherapy were considered. Furthermore, no pharmacokinetic difference was observed between stage III and IV patients who received epirubicin plus docetaxel (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The objective of this study was to examine the effects of the administration of either paclitaxel or docetaxel on the pharmacokinetics and metabolism of epirubicin. No change in the pharmacokinetic parameters of epirubicin was found when it was given immediately before either paclitaxel or docetaxel infusion. By contrast, differences were clearly evident in its metabolism: after a combination regimen with paclitaxel or docetaxel, epirubicin metabolism, assessed by comparing the AUCs of the metabolites, was generally more extensive than after single-agent anthracycline treatment. Moreover, some differences were noted between the effects that paclitaxel and docetaxel exerted on epirubicin metabolism.

Evidence of a statistically significant increase in EOL plasma levels emerged in the present study when epirubicin was followed by paclitaxel but not when epirubicin was followed by docetaxel. Plasma EOL concentrations rose rapidly during the 3-hour paclitaxel infusion, with peak concentration occurring after the end of paclitaxel treatment. The plasma exposure to EOL increased two-fold compared with the epirubicin-alone group. Although the pharmacokinetics of EOL were significantly modified by the administration of paclitaxel, they were not significantly influenced by the administration of docetaxel. However, the aglycone metabolite 7d-Aone as well as the metabolites sensitive to glucuronidase treatment that are likely glucuronides of epirubicin and EOL had a statistically significant increase in their plasma levels during the infusion of both the taxanes. The AUC of the plasma 7d-Aone increased 1.7-fold and 1.9-fold when epirubicin was administered with paclitaxel and docetaxel, respectively, compared with epirubicin given alone. Furthermore, patients who received epirubicin along with paclitaxel or docetaxel had greater glucuronidation of epirubicin and EOL compared with those treated with epirubicin alone. While our findings are consistent with those reported by others¹⁸ who also noted an increased glucuronidation of epirubicin and EOL exerted by paclitaxel, the high plasma exposure to both 7d-Aone and glucuronides, without altered plasma levels of both the parent drug and EOL, is a new observation in regard to the effects of docetaxel on epirubicin metabolism. Differences shown by paclitaxel and docetaxel in terms of EOL plasma levels and clearance patterns may depend on the formulations of the taxanes. Indeed, unlike the vehicle used to formulate docetaxel, Cremophor EL, the paclitaxel vehicle, is known to increase the bioavailability of doxorubicin and its major metabolite, DOL, in mice²⁷ and humans,²⁸ acting as a biologic active agent that can alter the pharmacokinetics of both paclitaxel²⁹ and anthracycline.²⁸ However, recent in vivo data indicate that Cremophor EL has little impact, if any, on the pharmacokinetics of the parent compound, epirubicin.^30,31 In addition, preclinical findings indicate that docetaxel and paclitaxel exert different activities in mice bearing tumor xenografts of parental human sarcoma³² and that they induce different interactions on the pharmacokinetics of epirubicin.³¹ Collectively, these observations uphold the assumption that both the different vehicles used and the different intrinsic properties of these taxanes have some influence on epirubicin metabolism.

What role the increased bioavailability of epirubicin metabolites plays in the antitumor activity and toxicity of the combination therapy can be hypothesized only after a discussion of the individual antitumor and cardiotoxic effects of epirubicin, doxorubicin, and their metabolites. Comparison of the pharmacokinetic and metabolic profiles of the two anthracyclines revealed that epirubicin is eliminated more rapidly than doxorubicin, possibly because of a difference in metabolic conversion.³³ Two important metabolic pathways were reported for the anthracyclines, namely, reductive deglycosidation and carbonyl reduction.³⁴ The C-13 carbonyl-reduced alcohol, referred to as DOL, and 7-deoxy-aglycones represent the major metabolites in the case of doxorubicin (Fig 4). Unlike the aglycone compounds that were reported to lack antitumor activity, DOL seems to maintain some antitumor properties and to largely contribute to cardiotoxicity.³⁵ Unlike doxorubicin, epirubicin and its metabolite EOL are converted into their glucuronic acid conjugates. These metabolites are inactive, and the glucuronidation pathway has been suggested to enhance excretion processes.³⁴ This unique glucuronidation of epirubicin and its rapid elimination could explain its reduced cardiotoxicity with respect to doxorubicin.

View larger version (25K): [in this window] [in a new window]   Fig 4. Major metabolic pathways of doxorubicin and epirubicin.

The pharmacokinetic interference between doxorubicin and paclitaxel, leading to increased bioavailability of both doxorubicin and its metabolite DOL, may have contributed to the clinical cardiotoxicity of this regimen.^7,17 If this were true, and if the same relationship that exists between doxorubicin and DOL also exists between EOL and epirubicin, then the increased bioavailability of EOL we observed in combination therapy with epirubicin and paclitaxel might be expected to increase the cardiotoxicity associated with epirubicin. However, the plasma exposure to both glucuronides and 7d-Aone metabolites was also significantly increased by paclitaxel. Although a clear role for these latter metabolites in the mechanism of action of either doxorubicin or epirubicin has not been completely defined, it has been suggested that an inverse relationship may exist between the formation of 7-deoxy-aglycones from epirubicin and the generation of cardiotoxic free radicals.²⁵ From these standpoints, the significantly altered routes of epirubicin metabolism induced by paclitaxel may result in a balance between cytotoxic and noncytotoxic metabolites. The lack of influence of docetaxel on both DOL²⁰ and EOL (present study) metabolic pathways, and the lack of cardiotoxicity reported with the use of docetaxel associated with either doxorubicin or epirubicin, would further reinforce this hypothesis.

Another important point is the relationship between the changes in epirubicin metabolism induced by taxanes and the antitumor activity. It could be speculated that the increased metabolism of epirubicin, and particularly its increased glucuronidation, may lead to a reduced activity of the drug. However, some data seem to indicate that this may not be the case. Evidence of an enhanced glucuronidation of epirubicin by the concomitant use of verapamil also emerged from a study conducted by Mross et al.³⁶ However, a randomized study conducted by the same group in advanced breast cancer patients comparing epirubicin alone versus epirubicin associated with verapamil reported the same response rate (near 30%) and toxicity in both arms.³⁷ Furthermore, clinical data from nonrandomized studies do not seem to indicate any negative effect: the objective response rates reported for the association of paclitaxel and epirubicin ranged from 44% to 84%,^10-12 and those of docetaxel and epirubicin ranged between 69% and 76%.^15,38,39 When the limits of noncomparative trials are taken into account, these results seem to be superimposable upon those obtained with the association of taxanes and doxorubicin. Therefore, at least in terms of activity, no clinical relevance could be demonstrated for the pharmacokinetic interactions between taxanes and epirubicin.

Our data show that there is no apparent pharmacokinetic interaction between either paclitaxel or docetaxel and parental epirubicin, whereas the metabolism of epirubicin is clearly affected by both taxanes. Moreover, levels and patterns of EOL concentrations in plasma differed considerably between the paclitaxel and docetaxel groups. Further clinical studies are required to verify whether changes in epirubicin metabolism may have clinical relevance in terms of toxicity and efficacy.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. 98.00488.CT04 from the Consiglio Nazionale per la Ricerca and grants from the Associazione Italiana per la Ricerca sul Cancro (to M. Venturini).

We are grateful to Dr A. Suarato and Dr E. Vanotti, who provided the epirubicin, EOL, and 7d-Aone standards, and to Thomas Wiley for his English translation of the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247-1259, 1990[Abstract/Free Full Text]

2. Ringel I, Horwitz SB: Studies with RP 56976 (taxotere): A semisynthetic analogue of taxol. J Natl Cancer Inst 83:288-291, 1991[Abstract/Free Full Text]

3. Huizing MT, Sewberath Misser VH, Pieters RC, et al: Taxanes: A new class of antitumor agents. Cancer Invest 13:381-404, 1995[Medline]

4. Siedman AD: The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res 1:247-256, 1995[Medline]

5. Ravdin PM, Valero V: Review of docetaxel (Taxotere), a highly active new agent for the treatment of metastatic breast cancer. Semin Oncol 22:17-21, 1995 (suppl 4)

6. Sledge GW Jr, Robert N, Sparano JA, et al: Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: The Eastern Cooperative Oncology Group experience. Semin Oncol 21:15-18, 1994 (suppl 8)

7. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995[Abstract]

8. Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7:687-693, 1996[Abstract/Free Full Text]

9. Bonadonna G, Gianni L, Santoro A, et al: Drugs ten years later: Epirubicin. Ann Oncol 4:359-369, 1993[Free Full Text]

10. Luck HJ, Thomsenn C, duBois A, et al: Interim analysis of a phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer. Semin Oncol 23:33-36, 1996 (suppl 1)

11. Catimel G, Spielman M, Dieras V, et al: Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer: A preliminary report on safety. Semin Oncol 23:24-27, 1996 (suppl 1)

12. Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15:2510-2517, 1997[Abstract/Free Full Text]

13. Chan S: Docetaxel vs doxorubicin in metastatic breast cancer resistant to alkylating chemotherapy. Oncology 11:19-24, 1997 (suppl 8) [Medline]

14. Bourgeois H, Gruia G, Dieras V, et al: Docetaxel (D) in combination with doxorubicin (Dx) as 1st line CT of metastatic breast cancer (MBC): A phase I dose finding study. Proc Am Soc Clin Oncol 15:148, 1996 (abstr 259)

15. Venturini M, Michelotti A, Papaldo P, et al: First line epirubicin (EPI) and taxotere (TXT) in advanced breast cancer: A phase I study. Proc Am Soc Clin Oncol 17:179a, 1998 (abstr 690)

16. Holmes FA, Madden T, Newman RA, et al: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 14:2713-2721, 1996[Abstract/Free Full Text]

17. Gianni L, Viganò L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15:1906-1915, 1997[Abstract/Free Full Text]

18. Gianni L, Viganò L, Locatelli A, et al: Different interference of paclitaxel (PTX) on human pharmacokinetics of doxorubicin (DOX) and epirubicin (EPI). Proc Am Soc Clin Oncol 16:224a, 1997 (abstr 786)

19. Bruno R, Hille D, Riva A, et al: Population pharmacokinetic/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998[Abstract/Free Full Text]

20. Bellott R, Robert J, Dieras V, et al: Taxotere does not change the pharmacokinetic profile of doxorubicin and doxorubicinol. Proc Am Soc Clin Oncol 17:221, 1998 (abstr 853)

21. Maessen PA, Mross KB, Pinedo HM, et al: Improved method for the determination of 4'-epidoxorubicin and seven metabolites in plasma by high-performance liquid chromatography. J Chromatogr 417:339-346, 1987[Medline]

22. Yamaoaka K, Nakagana T, Uno T: Application of Akaike information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 2:165-175, 1978

23. Gibaldi M, Perrier D: Pharmacokinetics (ed 2). New York, NY, Marcel Dekker, 1982

24. Jakobsen P, Steiness E, Bastholt L, et al: Multiple-dose pharmacokinetics of epirubicin at four different dose levels: Studies in patients with metastatic breast cancer. Cancer Chemother Pharmacol 28:63-68, 1991[Medline]

25. Mross K, Maessen P, van der Vijgh WJF, et al: Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 6:517-526, 1988[Abstract]

26. Jacobsen P, Sørensen B, Bastholt L, et al: The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil and tamoxifen in metastatic breast cancer patients. Cancer Chemother Pharmacol 35:45-52, 1994[Medline]

27. Webster LK, Cosson EJ, Stokes KH, et al: Effect of paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice. Br J Cancer 73:522-524, 1996[Medline]

28. Millward LK, Cosson EJ, Stokes KH, et al: Cremophor EL changes the pharmacokinetics of doxorubicin. Proc Am Assoc Cancer Res 36:373, 1995 (abstr 2221)

29. Sparreboom A, van Tellingen O, Nooijen WJ, et al: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 56:2112-2115, 1996[Abstract/Free Full Text]

30. Colombo T, Gonzalez Paz O, Zucchetti M, et al: Paclitaxel induces significant changes in epidoxorubicin distribution in mice. Ann Oncol 7:801-805, 1996[Abstract/Free Full Text]

31. D'Incalci M, Colombo T, Zucchetti M, et al: Pharmacokinetic interaction between taxanes and anthracyclines: In vivo study in mice. Proc Am Soc Clin Oncol 17:239a, 1998 (abstr 915)

32. Vanhoefer U, Cao S, Harstrick A, et al: Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein. Ann Oncol 8:1221-1228, 1997[Abstract/Free Full Text]

33. Weenen H, Lankelma J, Penders PGM, et al: Pharmacokinetics of 4'-epi-doxorubicin in man. Invest New Drugs 1:59-64, 1983[Medline]

34. Weenen H, Van Maanen JMS, De Planque MM, et al: Metabolism of 4'-modified analogs of doxorubicin: Unique glucuronidation pathway for 4'-epidoxorubicin. Eur J Cancer Clin Oncol 20:919-926, 1984[Medline]

35. Bachur NR: Biochemical pharmacology of the anthracycline antibiotics, Sartorelli AC (ed):Cancer Chemotherapy58-70Washington, DC, American Chemical Society, 1976

36. Mross K, Hamm K, Hossfeld DK: Effects of verapamil on the pharmacokinetics and metabolism of epirubicin. Cancer Chemother Pharmacol 31:369-375, 1993[Medline]

37. Mross K, Bohn C, Edler L, et al: Randomized phase II study of single-agent epirubicin +/- verapamil in patients with advanced metastatic breast cancer: An AIO clinical trial. Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. Ann Oncol 4:45-50, 1993[Abstract/Free Full Text]

38. Kerbrat P, Viens P, Rochè H, et al: Docetaxel in combination with epirubicin as 1^st line chemotherapy of metastatic breast cancer: Final results. Proc Am Soc Clin Oncol 17:151a, 1998 (abstr 579)

39. Trudeau ME, Crump M, Latreille J, et al: Escalating doses of docetaxel and epirubicin as a first line therapy for metastatic breast cancer: A phase I study of the National Cancer Institute of Canada Clinical Trials Group. Proc Am Soc Clin Oncol 17:178a, 1998 (abstr 687)

Submitted June 22, 1998; accepted December 8, 1998.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				G. Mantovani, C. Madeddu, C. Cadeddu, M. Dessi, A. Piras, E. Massa, R. Serpe, G. Antoni, and G. Mercuro 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 Oncologist, December 1, 2008; 13(12): 1296 - 1305. [Abstract] [Full Text] [PDF]

				G. Mercuro, C. Cadeddu, A. Piras, M. Dessi, C. Madeddu, M. Deidda, R. Serpe, E. Massa, and G. Mantovani Early Epirubicin-Induced Myocardial Dysfunction Revealed by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers Oncologist, September 1, 2007; 12(9): 1124 - 1133. [Abstract] [Full Text] [PDF]

				E. Salvatorelli, P. Menna, L. Gianni, and G. Minotti Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 790 - 800. [Abstract] [Full Text] [PDF]

				M. Sandstrom, H. Lindman, P. Nygren, E. Lidbrink, J. Bergh, and M.O. Karlsson Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer Patients J. Clin. Oncol., January 20, 2005; 23(3): 413 - 421. [Abstract] [Full Text] [PDF]

				J. Gligorov and J. P. Lotz Preclinical Pharmacology of the Taxanes: Implications of the Differences Oncologist, June 2, 2004; 9(suppl_2): 3 - 8. [Abstract] [Full Text] [PDF]

				G. Lunardi, M. O. Vannozzi, C. Bighin, L. Del Mastro, I. Stevani, G. Schettini, and M. Venturini Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients Ann. Onc., August 1, 2003; 14(8): 1222 - 1226. [Abstract] [Full Text] [PDF]

				D. Rischin, S. P. Ackland, J. Smith, M. B. Garg, S. Clarke, M. J. Millward, G. C. Toner, and J. Zalcberg Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics Ann. Onc., November 1, 2002; 13(11): 1810 - 1818. [Abstract] [Full Text] [PDF]

				S. H. Giordano, D. J. Booser, J. L. Murray, N. K. Ibrahim, Z. U. Rahman, V. Valero, R. L. Theriault, M. F. Rosales, E. Rivera, D. Frye, et al. A Detailed Evaluation of Cardiac Toxicity: A Phase II Study of Doxorubicin and One- or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer Clin. Cancer Res., November 1, 2002; 8(11): 3360 - 3368. [Abstract] [Full Text] [PDF]

				S. Fogli, R. Danesi, A. Gennari, S. Donati, P. F. Conte, and M. Del Tacca Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer Ann. Onc., June 1, 2002; 13(6): 919 - 927. [Abstract] [Full Text] [PDF]

				P. Vici, G. Colucci, V. Gebbia, A. Amodio, F. Giotta, F. Belli, F. Conti, N. Gebbia, G. Pezzella, M. R. Valerio, et al. First-Line Treatment With Epirubicin and Vinorelbine in Metastatic Breast Cancer J. Clin. Oncol., June 1, 2002; 20(11): 2689 - 2694. [Abstract] [Full Text] [PDF]

				G. Lunardi, M. Venturini, M. O. Vannozzi, G. Tolino, L. Del Mastro, C. Bighin, G. Schettini, and M. Esposito Influence of alternate sequences of epirubicin and docetaxel on the pharmacokinetic behaviour of both drugs in advanced breast cancer Ann. Onc., February 20, 2002; 13(2): 280 - 285. [Abstract] [Full Text] [PDF]

				G. Grasselli, L. Vigano, G. Capri, A. Locatelli, E. Tarenzi, C. Spreafico, A. Bertuzzi, A. Giani, C. Materazzo, S. Cresta, et al. Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic Breast Cancer J. Clin. Oncol., April 15, 2001; 19(8): 2222 - 2231. [Abstract] [Full Text] [PDF]

				J. A. Sparano, A. O'Neill, P. L. Schaefer, C. I. Falkson, and W. C. Wood Phase II Trial of Doxorubicin and Docetaxel Plus Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer: Eastern Cooperative Oncology Group Study E1196 J. Clin. Oncol., June 12, 2000; 18(12): 2369 - 2377. [Abstract] [Full Text] [PDF]

				M. Venturini, G. Lunardi, L. Del Mastro, M. O. Vannozzi, G. Tolino, G. Numico, M. Viale, I. Pastrone, C. Angiolini, G. Bertelli, et al. Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity J. Clin. Oncol., May 10, 2000; 18(10): 2116 - 2125. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Esposito, M. Articles by Rosso, R. Search for Related Content PubMed PubMed Citation Articles by Esposito, M. Articles by Rosso, R. Social Bookmarking                            What's this?