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

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).