Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins.
OBJECTIVE
Our objectives were to study the extent of docetaxel binding to plasma in the presence and absence of its excipient, polysorbate 80 (Tween 80; Imperial Chemical Industries PLC, London, United Kingdom), in vitro and to evaluate the pharmacokinetics of unbound docetaxel in vivo.


METHODS
Equilibrium dialysis was used for determination of the fraction unbound (f(u)) docetaxel and was applied to study the pharmacokinetic behavior of unbound docetaxel in 23 patients with cancer receiving an intravenous infusion of the drug formulated in polysorbate 80 (Taxotere; Aventis Pharma SA, Vitry-sur-Seine Cedex, France).


RESULTS
Polysorbate 80, added at clinically relevant concentrations (up to 1.0 microL/mL), increased f(u) in vitro by 13% (7.84% +/- 0.0752% versus 6.95% +/- 0.0678%, P <.00001). Similarly, f(u) calculated on the basis of the observed area under the plasma concentration-time curve (AUC) values [f(u)(AUC)] in vivo was 12% higher than f(u) in pretreatment samples [f(u)(pre)] (6.00% +/- 1.03% versus 5.49% +/- 1.01%, P =.038). Of various serum proteins evaluated, only alpha(1)-acid glycoprotein was significantly related to f(u) (P <.0018), with higher f(u) in the presence of lower protein levels. Total docetaxel clearance was related to alpha(1)-acid glycoprotein (R(2) = 0.13, P =.058), f(u)(pre) (R(2) = 0.15, P =.039), and f(u)(AUC) (R(2) = 0.29, P =.0048).


CONCLUSIONS
This study demonstrates that the plasma binding of docetaxel is influenced by both alpha(1)-acid glycoprotein and its formulation vehicle. Further investigation is required to resolve the potential clinical significance of these observations.
Loos
Walter J
WJ
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. w.loos@erasmusmc.nl
Baker
Sharyn D
SD
Verweij
Jaap
J
Boonstra
Joke G
JG
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D000077143:Docetaxel; D005079:Excipients; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009961:Orosomucoid / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011136:Polysorbates; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D001798:Blood Proteins; D005079:Excipients; D009961:Orosomucoid; D011136:Polysorbates; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel