Alpha(1)-acid glycoprotein, a
plasma protein that binds
docetaxel, is a significant determinant of the clearance and activity of
docetaxel, but its serum levels in
cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound
drug rather than total
drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound
docetaxel were investigated in
cancer patients.
Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound
docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total
docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound
docetaxel was calculated by multiplying fu by the AUC of total
docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound
drug were compared between patients who did or did not experience grade 4
neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4
neutropenia was observed in 24 patients. Although Cmax and AUC of total
drug were not different in patients with or without grade 4
neutropenia, patients who experienced grade 4
neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound
docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid
glycoprotein were determinants of grade 4
neutropenia. Pharmacokinetics of unbound
drug rather than total
drug is a better predictor of
neutropenia for
docetaxel.