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/m(2), epirubicin 90 mg/m(2) and paclitaxel 175 mg/m(2) (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m(2) and paclitaxel 175 mg/m(2) (EP, n = 6) and epirubicin 90 mg/m(2): 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 (E-max) 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 ng/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 mumol/l (tC(0.1)) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et-50) 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 pactitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine. RI Fogli, Stefano/G-8324-2011
Gemcitabine, epirubicin and paclitaxel: pharmacokinetlic and pharmacodynamic interactions in advanced breast cancer
Gennari, Alessandra
2002-01-01
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/m(2), epirubicin 90 mg/m(2) and paclitaxel 175 mg/m(2) (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m(2) and paclitaxel 175 mg/m(2) (EP, n = 6) and epirubicin 90 mg/m(2): 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 (E-max) 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 ng/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 mumol/l (tC(0.1)) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et-50) 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 pactitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine. RI Fogli, Stefano/G-8324-2011I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.