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/m(2)). 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 microg/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 microg.h/ml (at 660 mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was associated with the dose-limiting neutropenia in a maximum-effect model (R(2) = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2)) 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 ( approximately 4 liters) and slow systemic clearance ( approximately 0.11 liters/h).
|Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Docosahexaenoic Acids/*pharmacokinetics, Dose-Response Relationship, Drug, Female, Humans, Male, Middle aged, Models, Chemical, Neoplasms/*drug therapy, Paclitaxel/*pharmacokinetics/pharmacology/therapeutic use, Protein Binding, Research Support, Non-U.S. Gov't, Time Factors|
|Clinical Cancer Research|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Sparreboom, A, Wolff, A.C, Verweij, J, Zabelina, Y, van Zomeren, D.M, McIntire, G.L, … Baker, S.D. (2003). Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies. Clinical Cancer Research. Retrieved from http://hdl.handle.net/1765/10060