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

S. Fogli, R. Danesi, A. Gennari, S. Donati, P. F. Conte, M. Del Tacca

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 × 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 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.

Original languageEnglish
Pages (from-to)919-927
Number of pages9
JournalAnnals of Oncology
Volume13
Issue number6
DOIs
Publication statusPublished - 2002

Fingerprint

gemcitabine
Epirubicin
Paclitaxel
Pharmacokinetics
Breast Neoplasms
Neutropenia
Pharmaceutical Preparations
Kidney

Keywords

  • Bone marrow
  • Drug interactions
  • Gemcitabine-epirubicin-paclitaxel
  • Pharmacokinetics
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gemcitabine, epirubicin and paclitaxel : Pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. / Fogli, S.; Danesi, R.; Gennari, A.; Donati, S.; Conte, P. F.; Del Tacca, M.

In: Annals of Oncology, Vol. 13, No. 6, 2002, p. 919-927.

Research output: Contribution to journalArticle

Fogli, S. ; Danesi, R. ; Gennari, A. ; Donati, S. ; Conte, P. F. ; Del Tacca, M. / Gemcitabine, epirubicin and paclitaxel : Pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. In: Annals of Oncology. 2002 ; Vol. 13, No. 6. pp. 919-927.
@article{6f64ef9f9bf9459fb82e752cd736a7dc,
title = "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 × 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 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.",
keywords = "Bone marrow, Drug interactions, Gemcitabine-epirubicin-paclitaxel, Pharmacokinetics, Toxicity",
author = "S. Fogli and R. Danesi and A. Gennari and S. Donati and Conte, {P. F.} and {Del Tacca}, M.",
year = "2002",
doi = "10.1093/annonc/mdf164",
language = "English",
volume = "13",
pages = "919--927",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "NLM (Medline)",
number = "6",

}

TY - JOUR

T1 - Gemcitabine, epirubicin and paclitaxel

T2 - Pharmacokinetic and pharmacodynamic interactions in advanced breast cancer

AU - Fogli, S.

AU - Danesi, R.

AU - Gennari, A.

AU - Donati, S.

AU - Conte, P. F.

AU - Del Tacca, M.

PY - 2002

Y1 - 2002

N2 - 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 × 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 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.

AB - 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 × 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 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.

KW - Bone marrow

KW - Drug interactions

KW - Gemcitabine-epirubicin-paclitaxel

KW - Pharmacokinetics

KW - Toxicity

UR - http://www.scopus.com/inward/record.url?scp=0035990106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035990106&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdf164

DO - 10.1093/annonc/mdf164

M3 - Article

C2 - 12123338

AN - SCOPUS:0035990106

VL - 13

SP - 919

EP - 927

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 6

ER -