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Disposition of Docosahexaenoic Acid-Paclitaxel, a Novel Taxane, in Blood

In Vitro and Clinical Pharmacokinetic Studies¹

Department of Medical Oncology, Erasmus MC—Daniel den Hoed Cancer Center, 3075 EA Rotterdam, the Netherlands [A. S., J. V., D. M. v. Z.]; Divisions of Medical Oncology [A. C. W., R. C. D.] and Experimental Therapeutics [Y. Z., S. D. B.], The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231; and Protarga, Inc., King of Prussia, Pennsylvania 19406 [G. L. M., C. S. S.]

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 nonspecific, 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).

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