Effect of cyclosporin A on protein binding of teniposide in cancer patients

Giuseppe Toffoli, Paola Aita, Roberto Sorio, Giuseppe Corona, Antonella Bertola, Anna Maria Colussi, Isabelle Robieux, Mauro Boiocchi

Research output: Contribution to journalArticle

Abstract

We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p = 0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC(0-∞)) and free VM26 AUC(0-∞) increased after treatment with CSA, but the median increase in free AUC(0-∞) was higher (2.7-fold) than total AUC(0-∞) (1.5-fold) (p = 0.04). Bilirubin was significantly (p <0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/μl, range <100-2860/μl) was lower than after VM26 alone (median 1900/μl, range 200-6000/μl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC(0-∞) VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC(0-∞) VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.

Original languageEnglish
Pages (from-to)511-518
Number of pages8
JournalAnti-Cancer Drugs
Volume10
Issue number6
Publication statusPublished - 1999

Keywords

  • Cyclosporin
  • Protein binding
  • Teniposide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

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    Toffoli, G., Aita, P., Sorio, R., Corona, G., Bertola, A., Colussi, A. M., Robieux, I., & Boiocchi, M. (1999). Effect of cyclosporin A on protein binding of teniposide in cancer patients. Anti-Cancer Drugs, 10(6), 511-518.