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/m2 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 mean (+/-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 , AUC, and clearance values of 451 +/- 221 microg/mL, 528 +/- 217 microg/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 AUC and liver impairment were significantly associated with unbound docetaxel clearance. Both unbound docetaxel AUC and total AUC 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.
Baker
Sharyn D
SD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA. sdbaker@jhmi.edu
Li
Jing
J
ten Tije
Albert J
AJ
Figg
William D
WD
Graveland
Wilfried
W
Verweij
Jaap
J
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced* / Q000145:classification; D012720:Severity of Illness Index; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel