Taxotere® (docetaxel) Injection Concentrate: Pharmacokinetics profile
Taxotere® has a linear pharmacokinetic profile1,2
The pharmacokinetics of Taxotere® have been evaluated in cancer patients
after administration of 20–115 mg/m² in phase I studies. The area under the
curve (AUC) was dose proportional following doses of 70–115 mg/m² with infusion
times of 1 to 2 hours.
The pharmacokinetic profile of Taxotere® is consistent with a 3-compartment
pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 minutes,
36 minutes, and 11.1 hours, respectively.
Distribution
The initial rapid decline represents distribution to the peripheral compartments
and the late (terminal) phase is due, in part, to a relatively slow efflux of Taxotere®
from the peripheral compartment. Mean values for total body clearance and steady
state volume of distribution were 21 L/h/m² and 113 L, respectively. In vitro
studies show that Taxotere® is approximately 94% bound to plasma
proteins, primarily to albumin, α1-acid glycoproteins, and lipoproteins.
Population pharmacokinetics1
A population pharmacokinetic analysis was carried out after Taxotere®
treatment of 535 patients dosed at 100 mg/m². Pharmacokinetic parameters estimated
by this analysis were very close to those estimated from phase I studies. The pharmacokinetics
of Taxotere® were not influenced by age or gender and total body
clearance of Taxotere® was not modified by pretreatment with dexamethasone.
In patients with clinical chemistry data suggestive of mild to moderate liver function
impairment (AST and/or ALT >1.5 times the upper limit of normal [ULN] concomitant
with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an
average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average,
however, includes a substantial range and there is, at present, no measurement that
would allow recommendation for dose adjustment in such patients.
Patients with combined abnormalities of transaminase and alkaline phosphatase should
not be treated with Taxotere®. Patients with severe hepatic impairment
have not been studied.
Mean total body clearance for Japanese patients dosed at the range of 10–90 mg/m²
was similar to that of European/American populations dosed at 100 mg/m², suggesting
no significant difference in the elimination of Taxotere® in the
2 populations.
Taxotere® total body clearance was not modified by pre-treatment
of dexamethasone.
Clearance of Taxotere® in combination therapy with cisplatin was
similar to that previously observed following Taxotere® monotherapy.
The pharmacokinetic profile of cisplatin in combination therapy with Taxotere®
was similar to that observed with cisplatin alone.
The combined administration of Taxotere®, cisplatin, and fluorouracil
in 12 patients with solid tumors had no influence on the pharmacokinetics of each
individual drug.
A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory
metastatic prostate cancer indicated that systemic clearance of Taxotere®
in combination with prednisone is similar to that observed following administration
of Taxotere® alone.
Elimination
A study of 14C-docetaxel was conducted in 3 cancer patients. The Taxotere®
metabolite was formed by oxidative metabolism of the tert-butyl ester group. Within
7 days after IV administration, approximately 75% of the drug was excreted in the
feces and 6% in the urine. About 80% of the radioactivity recovered in feces was
excreted during the first 48 hours as 1 major and 3 minor metabolites with very
small amounts (less than 8%) of unchanged drug.