Relationship of systemic exposure to unbound docetaxel and neutropenia

Objective: Our objective was to evaluate the association between exposure to unbound docetaxel and neutropenia in patients with cancer and to identify factors influencing unbound docetaxel clearance. Methods: Docetaxel was administered once every 3 weeks at a dose of 75 mg/m(2) to 49 patients with normal liver function (n = 40, group 1) or mild elevations in liver function test results (n = 9, group 2) or at a dose of 50 mg/m(2) to patients with moderate elevations in liver function test results (n = 6, group 3). Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy. Total docetaxel concentrations were determined by HPLC and tandem mass spectrometry, and unbound docetaxel fraction was determined by equilibrium dialysis. Results: In patients with normal liver function, unbound docetaxel disposition was characterized by me-an (+/-SD) maximum plasma concentration (C-max), area under the curve (AUC), and clearance values of 233 +/- 101 ng/mL, 32 +/- 143 ng/mL (.) h, and 565 +/- 329 L/h, respectively. Unbound clearance varied 8.5-fold; polysorbate 80 exhibited mean (+/-SD) C-max, and clearance values of 451 +/- 221 mug/mL, 528 +/- 217 mug/mL (.) h, and 8.18 +/- 3.66 L/h, respectively; and clearance varied 6.7-fold. Unbound docetaxel clearance was reduced in patients with moderate liver impairment (groups 1 and 2 versus group 3, P = .020). From multiple linear regression analysis, only polysorbate 80 AUG and liver impairment were significantly associated with unbound docetaxel clearance. Both unbound docetaxel AUG and total AUG were correlated with the percentage decrements in absolute neutrophil count (P = .002 and P = .029, respectively), as well as the worst grade of neutropenia (P = .013 and P = .220, respectively), where higher exposure was associated with worse hematologic toxicity. Conclusions: Exposure to unbound docetaxel is closely related to drug-induced hematologic toxicity and should be considered in future pharmacologic investigations.