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Clinical pharmacokinetics of unbound docetaxel: Role of polysorbate 80 and serum proteins
Author(s) -
Loos Walter J.,
Baker Sharyn D.,
Verweij Jaap,
Boonstra Joke G.,
Sparreboom Alex
Publication year - 2003
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(03)00222-4
Subject(s) - docetaxel , pharmacokinetics , pharmacology , polysorbate , chemistry , in vivo , paclitaxel , blood proteins , orosomucoid , chromatography , medicine , glycoprotein , chemotherapy , biochemistry , pulmonary surfactant , microbiology and biotechnology , biology
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 μL/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 α 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 α 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). Conclusion This study demonstrates that the plasma binding of docetaxel is influenced by both α 1 ‐acid glycoprotein and its formulation vehicle. Further investigation is required to resolve the potential clinical significance of these observations. Clinical Pharmacology & Therapeutics (2003) 74 , 364–371; doi: 10.1016/S0009‐9236(03)00222‐4