Annals of Oncology 13:919-927, 2002
© 2002 European Society for Medical Oncology
Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer
1Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa; 2Division of Medical Oncology, University Hospital, Pisa, Italy
Received 18 June 2001; revised 14 December 2001; accepted 17 January 2002.
Abstract
Background
The objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2',2'-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer.
Patients and methods
The drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin 90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model.
Results
Paclitaxel administration significantly increased the epirubicinol area under the concentration–time curve, from 357 ± 146 (epirubicin) to 603 ± 107 (EP) and 640 ± 81 h x 
g/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 µmol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP.
Conclusions
Paclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine.
Key words: bone marrow, drug interactions, gemcitabine–epirubicin–paclitaxel, pharmacokinetics, toxicity
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