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 SO;(Taxotere; Aventis Pharma:SA, Vitry-sur-Seine Cedex, France). Results: Polysorbate 80, added at clinically :relevant concentration(up to 1.0 muL/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 = 0.38). Of various serum proteins evaluated, only alpha(1)-acid glycoprotein was significantly related to f(U) (P < .0018), with higher f(U) in the protein levels. Total,docetaxel clearance was related to alpha(1)-acid glycoprotein (R-2 = 0.13, P = .058)f(U)(pre) 4(R-2 = 0.15, P-.039), and f(U)(;AUC) (R-2 = 0.29, P = .0048). Conclusion: This study,demonstrates that the,plasma binding of docetaxel is influenced by bofh alpha(1),-acid glycoprotein and its formulation vehicle.;Further investigation is required to resolve the potential clinical :significance of these observations.