Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer.

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 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 micromol/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.

• Authors: S Fogli, R Danesi, A Gennari, S Donati, P F Conte, M Del Tacca
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 13 Issue 6 Pg. 919-27 (Jun 2002) ISSN: 0923-7534 [Print] England
• PMID: 12123338 (Publication Type: Clinical Trial, Comparative Study, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Deoxycytidine
• Epirubicin
• Paclitaxel
• Gemcitabine

Topics

• Adult
• Analysis of Variance
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacokinetics)
• Biopsy, Needle
• Breast Neoplasms (drug therapy, pathology)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions
• Epirubicin (administration & dosage, pharmacokinetics)
• Female
• Humans
• Middle Aged
• Neoplasm Staging
• Paclitaxel (administration & dosage, pharmacokinetics)
• Probability
• Prognosis
• Treatment Outcome
• Gemcitabine