Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients

Robert Fruscio, Andrea A. Lissoni, Roberta Frapolli, Silvia Corso, Costantino Mangioni, Maurizio D'Incalci, Massimo Zucchetti

Research output: Contribution to journalArticle

Abstract

Introduction: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. α1-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. Patients and methods: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. Results: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C max and AUC 0-last of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC0-last showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. Conclusion: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.

Original languageEnglish
Pages (from-to)319-325
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume58
Issue number3
DOIs
Publication statusPublished - Sep 2006

Fingerprint

Pharmacokinetics
Clindamycin
Paclitaxel
Ovarian Neoplasms
Glycoproteins
Acids
Pharmaceutical Preparations
Plasmas
Chemotherapy
Acute-Phase Proteins
Carboplatin
Tissue Distribution
Drug Combinations
Cytotoxicity
Protein Binding
Consolidation
Surgery
Area Under Curve
Toxicity
Blood Proteins

Keywords

  • α-acid glycoprotein
  • Clindamycin
  • Ovarian cancer
  • Paclitaxel
  • Pharmacokinetics
  • Protein binding

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this

Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients. / Fruscio, Robert; Lissoni, Andrea A.; Frapolli, Roberta; Corso, Silvia; Mangioni, Costantino; D'Incalci, Maurizio; Zucchetti, Massimo.

In: Cancer Chemotherapy and Pharmacology, Vol. 58, No. 3, 09.2006, p. 319-325.

Research output: Contribution to journalArticle

Fruscio, Robert ; Lissoni, Andrea A. ; Frapolli, Roberta ; Corso, Silvia ; Mangioni, Costantino ; D'Incalci, Maurizio ; Zucchetti, Massimo. / Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 58, No. 3. pp. 319-325.
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AU - Fruscio, Robert

AU - Lissoni, Andrea A.

AU - Frapolli, Roberta

AU - Corso, Silvia

AU - Mangioni, Costantino

AU - D'Incalci, Maurizio

AU - Zucchetti, Massimo

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AB - Introduction: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. α1-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. Patients and methods: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. Results: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C max and AUC 0-last of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC0-last showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. Conclusion: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.

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