Inter-relationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients

Lia Van Zuylen, Luca Gianni, Jaap Verweij, Klaus Mross, Eric Brouwer, Walter J. Loos, Alex Sparreboom

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p <0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2 = 0.733; p = 0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations. (C) 2000 Lippincott Williams and Wilkins.

Original languageEnglish
Pages (from-to)331-337
Number of pages7
JournalAnti-Cancer Drugs
Volume11
Issue number5
DOIs
Publication statusPublished - 2000

Fingerprint

Paclitaxel
Neoplasms
Pharmacokinetics
Appointments and Schedules
Pharmaceutical Preparations
Castor Oil
cremophor EL
Surface-Active Agents
Erythrocytes
Water

Keywords

  • Cremophor EL
  • Non-linear pharmacokinetics
  • Paclitaxel

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Inter-relationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients. / Van Zuylen, Lia; Gianni, Luca; Verweij, Jaap; Mross, Klaus; Brouwer, Eric; Loos, Walter J.; Sparreboom, Alex.

In: Anti-Cancer Drugs, Vol. 11, No. 5, 2000, p. 331-337.

Research output: Contribution to journalArticle

Van Zuylen, Lia ; Gianni, Luca ; Verweij, Jaap ; Mross, Klaus ; Brouwer, Eric ; Loos, Walter J. ; Sparreboom, Alex. / Inter-relationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients. In: Anti-Cancer Drugs. 2000 ; Vol. 11, No. 5. pp. 331-337.
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