1 Department of PharmacologyPharmacotoxicology Laboratory, 2 Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
Received 10 December 2002; revised 20 March 2003; accepted 6 May 2003
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Abstract |
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Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites.
Patients and methods:
Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m2 i.v. bolus followed by docetaxel 75 mg/m2 in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m2, then 2 mg/m2 weekly thereafter) in a 30-min infusion. Epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin).
Results:
No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentrationtime curve (AUC024 h) was 1230 ± 318 [mean ± standard deviation (SD)] at the first cycle and 1287 ± 385 h·µg/l at the sixth. The mean (±SD) maximum plasma concentration (Cmax) and the terminal elimination half-life at the first cycle (1303 ± 490 µg/l and 12.5 ± 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 ± 580 µg/l and 11.5 ± 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference.
Conclusion:
Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.
Key words: advanced breast cancer, epirubicin, pharmacokinetic, trastuzumab
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Introduction |
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HER2 is a marker of aggressive disease forms, and is intrinsically involved in the development and maintenance of breast cancer. These features, together with the fact that HER2 is a membrane-associated receptor, made it an ideal candidate for targeted therapy. A humanized monoclonal antibody, trastuzumab, was developed and clinical trials started in early 1990. Trastuzumab inhibited tumor growth when used alone, but had synergistic or additive effects when used in combination with several antineoplastic agents [3]. Efficacy was clearly documented in metastatic breast cancer patients. Slamon et al. [4] showed that the addition of trastuzumab to chemotherapy was associated with significantly better responses and longer survival than chemotherapy alone. The most serious complication of trastuzumab was cardiotoxicity, especially when it was administered in combination with anthracyclines. Reported incidences of 28% (40/143) and 19% (27/143) of these cases were categorized as New York Heart Association (NYHA) class III or IV, respectively. The development of cardiotoxicity was unexpectedly high and had not been reported in early studies of trastuzumab as a single agent or in studies of combination treatment in animals.
The mechanism by which trastuzumab treatment leads to an increased incidence of cardiac dysfunction in patients treated with anthracyclines has not yet been defined, but could include any of the following: immune-mediated destruction of cardiomyocytes, drugdrug interaction with anthracyclines, defects in ErbB2 signaling required for maintenance of cardiac contractility, interference with cardiomyocyte survival signals, or indirect consequences of trastuzumab-mediated effects outside the heart [5].
Cardiotoxicity induced by anthracyclines may be exacerbated by pharmacokinetic interactions between some drugs. For instance, clinical pharmacological findings have shown that paclitaxel influences the pharmacokinetic behavior of doxorubicin when delivered in both 24- and 3-h infusions [6, 7]. Generally, paclitaxel induces a higher plasma concentration of both doxorubicin and its main cardiotoxic metabolite, doxorubicinol. Therefore, exploring possible pharmacokinetic interactions between trastuzumab and anthracyclines, as a potential explanation of the clinical findings, is clearly warranted [8].
Due to its decreased cardiotoxicity, epirubicin has replaced doxorubicin in recent clinical trials, and the association of epirubicin and docetaxel has been demonstrated not to be more cardiotoxic than epirubicin alone [9]. This was essentially explained by the absence of pharmacokinetic interference between docetaxel and epirubicin [10, 11].
The objective of the present study was to investigate the interactions of trastuzumab administration on the pharmacokinetics of epirubicin and its metabolites.
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Patients and methods |
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Patient selection
Patients affected by metastatic breast cancer that overexpressed HER2 were eligible for the study. The level of expression of HER2 was determined by immunohistochemical analysis (Hercept Test). Only patients with a score of 2+ or 3+ were eligible. Other eligibility criteria were performance status <1, 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. A normal left ventricular ejection fraction (LVEF) evaluated by angioscintigraphy (MUGA scan) was also required.
Treatment plan and drug administration
Epirubicin plus docetaxel administration. Based on our previous experience [9, 12], chemotherapy consisted of epirubicin 75 mg/m2 given as an i.v. bolus immediately followed by docetaxel 75 mg/m2 in a 1-h infusion. Cycles were repeated every 3 weeks. A maximum of eight cycles were planned.
Trastuzumab administration. Trastuzumab 4 mg/m2 was administered in a 90-min infusion on the first administration, and 2 mg/m2 in a 30-min infusion on the following administrations. Trastuzumab was administered weekly and continued until disease progression.
On day 1 of the first cycle of chemotherapy, patients received epirubicin plus docetaxel administration, and trastuzumab was administered 1 day later. On day 1 of the following cycles, trastuzumab was administered immediately before the epirubicin and docetaxel regimen administration.
Epirubicin, purchased as a sterile lyophilized powder in 50-mg vials, was dissolved in 25 ml of normal saline, and administered intravenously over 10 min.
Docetaxel, purchased as a sterile solution in vials containing 80 mg, was dissolved in 2 ml polysorbate 80 (Tween 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 h immediately after the epirubicin injection. The premedication schedule consisted of prednisone 50 mg starting 12 h before and continuing for 36 h after 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 i.v. the day of chemotherapy as antiemetic treatment.
Roche (Milan, Italy) supplied trastuzumab as a freeze-dried preparation at a nominal quantity of 150 mg in a single-dose vial for parenteral administration (powder for solution for infusion). For intravenous administration, each vial was reconstituted with 7.0 ml of sterile water for injection, yielding a solution of 22 mg/ml trastuzumab. Reconstituted trastuzumab was then added to 250 ml of 0.9% sodium chloride for injection and infused.
In order to prevent clinically significant cardiotoxicity, patients were followed using a MUGA scan at baseline: every two cycles during chemotherapy, and every 3 months during treatment with trastuzumab alone. Patients were removed from the treatment regimen if they developed cardiac toxicity as defined previously [13].
Pharmacokinetic studies
Each patient underwent pharmacokinetic analysis on day 1 of the first cycle of chemotherapy [i.e. epirubicin plus docetaxel administration alone (ED) group] and on day 1 of the sixth cycle of chemotherapy [i.e. trastuzumab administered immediately before the epirubicin plus docetaxel administration (TED) group)]. Each patient, therefore, acted as their own control.
For plasma analysis of epirubicin and its metabolites, heparinized venous blood samples were collected before treatment and at various times thereafter. Plasma samples were obtained at 5, 15, 30 and 60 min, and at 2, 3, 4, 6 and 24 h following epirubicin i.v. bolus. Blood samples were centrifuged immediately at room temperature, and plasma was separated and stored in aliquots at 20°C until analysis.
Sample analysis and pharmacokinetic calculations
Concentrations of epirubicin and its metabolites in plasma were determined as described previously [10] according to Maessen et al. [14]. The pharmacokinetics of the epirubicin metabolites epirubicinol (EOL), 7-deoxydoxorubicinone (7d-Aone), epirubicinol-glucuronide (EOL-glu) and epirubicin-glucuronide (EPI-glu) were evaluated.
All pharmacokinetic data were analyzed using an integrated computer system (Siphar program, Simed) on an IBM/IC computer. Values obtained by non-compartmental analysis (statistical moment theory) were considered, and the maximum peak plasma concentration (Cmax) was put on par with the mean concentration in the plasma samples following drug administration. Pharmacokinetic parameters were calculated using standard formulas [15]. Because it was demonstrated that the pharmacokinetics of epirubicin is at least linear for doses up to 150 mg/m2 [16], in the case of dose reduction at the sixth cycle, pharmacokinetic data were normalized for higher doses of epirubicin, i.e. 75 mg/m2.
Statistical analysis
Pharmacokinetic data were compared using the non-parametric Wilcoxon matched-pairs signed-ranks test for paired data. A probability of P < 0.05 was considered significant. Version 5.0.1 of SPSS for Windows software was used for the statistical analysis.
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Results |
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Main patient characteristics are listed in Table 1.
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Pharmacokinetic data of epirubicin (mean ± SD) evaluated in these four patients at the first and sixth cycles of chemotherapy were, respectively, Cmax 1203 ± 657 and 1053 ± 587 µg/l, AUC024 h 1201 ± 410 and 1320 ± 375 hµg/l, CL 67.6 ± 20.9 and 60.2 ± 16.1 l/h/m2, and telim 13.5 ± 3.8 and 11.7 ± 4.0 h.
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Discussion |
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We evaluated the effects of trastuzumab on epirubicin pharmacokinetics in patients receiving an epirubicin plus docetaxel regimen. This regimen was chosen on the basis of both our previous clinical experience and on the lack of pharmacokinetic interactions between anthracycline and taxane. In fact, we had previously shown that the docetaxel administration with epirubicin did not influence epirubicin and epirubicinol pharmacokinetics when compared with treatment using epirubicin alone [10]. Therefore, we could study the interactions of trastuzumab on epirubicin pharmaco-kinetics even though the anthracycline was combined with the taxane.
Moreover, we chose to evaluate epirubicin pharmacokinetics after six cycles on the basis of the long terminal half-life of trastuzumab and the time needed to achieve steady-state plasma concentration [20]. Trastuzumab plasma concentrations after 16 weeks are close to the concentrations seen at steady-state, which should be achieved after 20 weeks of weekly administration [20].
We enrolled only seven patients in the study, a relatively small sample size. All the pharmacokinetic parameters of epirubicin and its metabolites evaluated were quite similar at baseline compared to those at the sixth cycle, and P values were far from significant. Moreover, we were not able to find evidence for any trends in other directions. On the other hand, when a drugdrug interaction such as occurred here is evident, e.g. between paclitaxel and doxorubicin, eight patients is a sufficient number to highlight this interaction [6].
Our data are supported further by the fact that no pharmacokinetic interaction was observed in patients who experienced cardiotoxicity. In fact, we were not only able to observe any significant difference in epirubicin pharmacokinetics using the intra-patient evaluation, but we were also able to observe no effect when comparing patients with cardiotoxicity with those without (data not shown).
Our results did not show any interaction determined by trastuzumab on epirubicin pharmacokinetics; therefore it is unlikely that the increased cardiotoxicity observed with the association of trastuzumab and anthracyclines is due to changes in anthracycline pharmacokinetics.
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Acknowledgements |
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Footnotes |
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References |
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