| Indication |
For the treatment of patients with locally advanced or metastatic
breast cancer after failure of prior chemotherapy. Also used as a single
agent in the treatment of patients with locally advanced or metastatic
non-small cell lung cancer after failure of prior platinum-based
chemotherapy. Lastly, for use, in combination with prednisone, in the
treatment of patients with androgen independent (hormone refractory)
metastatic prostate cancer. |
| Pharmacodynamics |
Docetaxel is a taxoid antineoplastic agent. It promotes the
assembly of microtubules from tubulin dimers and stabilizes microtubules
by preventing depolymerization. This stability results in the
inhibition of the normal dynamic reorganization of the microtubule
network that is essential for vital interphase and mitotic cellular
functions. In addition, docetaxel induces abnormal arrays or "bundles"
of microtubules throughout the cell cycle and multiple asters of
microtubules during mitosis. |
| Mechanism of action |
Docetaxel interferes with the normal function of microtubule
growth. Whereas drugs like colchicine cause the depolymerization of
microtubules in vivo, docetaxel arrests their function by having the
opposite effect; it hyper-stabilizes their structure. This destroys the
cell's ability to use its cytoskeleton in a flexible manner.
Specifically, docetaxel binds to the β-subunit of tubulin. Tubulin is
the "building block" of mictotubules, and the binding of docetaxel locks
these building blocks in place. The resulting microtubule/docetaxel
complex does not have the ability to disassemble. This adversely affects
cell function because the shortening and lengthening of microtubules
(termed dynamic instability) is necessary for their function as a
transportation highway for the cell. Chromosomes, for example, rely upon
this property of microtubules during mitosis. Further research has
indicated that docetaxel induces programmed cell death (apoptosis) in
cancer cells by binding to an apoptosis stopping protein called Bcl-2
(B-cell leukemia 2) and thus arresting its function. |
| Absorption |
Not Available |
| Volume of distribution |
|
| Protein binding |
About 94% protein bound, mainly to a1-acid glycoprotein, albumin, and lipoproteins. |
| Metabolism |
Hepatic. In vitro drug interaction studies revealed that
docetaxel is metabolized by the CYP3A4 isoenzyme (1 major, 3 minor
metabolites). |
| Route of elimination |
Docetaxel was eliminated in both the urine and feces following
oxidative metabolism of the tert-butyl ester group, but fecal excretion
was the main elimination route. Within 7 days, urinary and fecal
excretion accounted for approximately 6% and 75% of the administered
radioactivity, respectively. |
| Half life |
Dose-dependent. Doses of 70 mg per square meter of body surface
area (mg/m 2 ) or higher produce a triphasic elimination profile. With
lower doses, assay limitations precluded detection of the terminal
elimination phase. Alpha (distribution) 4 minutes. Beta 36 minutes.
Gamma (terminal) 11.1 hours. |
| Clearance |
- 21 L/h/m2 [Cancer patients after IV administration of 20–115 mg/m2]
|
| Toxicity |
Oral LD50 in rat is >2000 mg/kg. Anticipated
complications of overdosage include: bone marrow suppression, peripheral
neurotoxicity, and mucositis. In two reports of overdose, one patient
received 150 mg/m2 and the other received 200 mg/m2
as 1-hour infusions. Both patients experienced severe neutropenia, mild
asthenia, cutaneous reactions, and mild paresthesia, and recovered
without incident. |
