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


METHODS
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).
Sparreboom
Alex
A
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 3075 EA Rotterdam, the Netherlands.
Wolff
Antonio C
AC
Verweij
Jaap
J
Zabelina
Yelena
Y
van Zomeren
Desiree M
DM
McIntire
Gregory L
GL
Swindell
Charles S
CS
Donehower
Ross C
RC
Baker
Sharyn D
SD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004281:Docosahexaenoic Acids / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D013997:Time Factors
D004281:Docosahexaenoic Acids; D017239:Paclitaxel