Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins
In: Clinical Pharmacology and Therapeutics, Jg. 74 (2003), S. 364-371
Online
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Zugriff:
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 (fu) 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 fu in vitro by 13% (7.84% ± 0.0752% versus 6.95% ± 0.0678%, P < .00001). Similarly, fu calculated on the basis of the observed area under the plasma concentration–time curve (AUC) values [fu(AUC)] in vivo was 12% higher than fu in pretreatment samples [fu(pre)] (6.00% ± 1.03% versus 5.49% ± 1.01%, P = .038). Of various serum proteins evaluated, only α1-acid glycoprotein was significantly related to fu (P < .0018), with higher fu in the presence of lower protein levels. Total docetaxel clearance was related to α1-acid glycoprotein (R2 = 0.13, P = .058), fu(pre) (R2 = 0.15, P = .039), and fu(AUC) (R2 = 0.29, P = .0048). Conclusion This study demonstrates that the plasma binding of docetaxel is influenced by both α1-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
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Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins
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Autor/in / Beteiligte Person: | Sparreboom, Alex ; Loos, Walter J. ; Boonstra, Joke G. ; Verweij, Jaap ; Baker, Sharyn D. ; Oncology, Medical |
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Zeitschrift: | Clinical Pharmacology and Therapeutics, Jg. 74 (2003), S. 364-371 |
Veröffentlichung: | Wiley-Blackwell, 2003 |
Medientyp: | unknown |
ISSN: | 1532-6535 (print) ; 0009-9236 (print) |
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