Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: In vitro and clinical pharmacokinetic studies

Alex Sparreboom, Antonio C. Wolff, Jaap Verweij, Yelena Zabelina, Desiree M. Van Zomeren, Gregory L. McIntire, Charles S. Swindell, Ross C. Donehower, Sharyn D. Baker

Research output: Contribution to journalArticlepeer-review


Purpose: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2′-position of paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. Experimental Design: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m2). Results: In vitro, DHA-paclitaxel was found to bind extensively to human plasma (99.6 ± 0.057%). The binding was concentration independent (P = 0.63), indicating a non-specific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 ± 0.0018 to 0.055 ± 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0-1000 μg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (± SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 ± 0.029 μg·h/ml (at 660 mg/m2) to 0.624 ± 0.216 μg·h/ml (at 1100 mg/m2), and was associated with the dose-limiting neutropenia in a maximum-effect model (R2 = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m2) is similar to that achieved with paclitaxel on clinically relevant dose schedules. Conclusions: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution (∼4 liters) and slow systemic clearance (∼0.11 liters/h).

Original languageEnglish (US)
Pages (from-to)151-159
Number of pages9
JournalClinical Cancer Research
Issue number1 I
StatePublished - Jan 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: In vitro and clinical pharmacokinetic studies'. Together they form a unique fingerprint.

Cite this