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.

pharmacology

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.

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.

biotransformation

Hepatic. In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme (1 major, 3 minor metabolites).

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.

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.

drug interactions

Aprepitant: Aprepitant may change levels of the chemotherapy agent, docetaxel.

Carboplatin: Platinum derivatives such as carboplatin may enhance the myelosuppressive effect of taxane derivatives such as docetaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity. Administering the taxane derivative before the platinum derivative seems prudent.

Cisplatin: Platinum derivatives such as cisplatin may enhance the myelosuppressive effect of taxane derivatives such as docetaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity. Administer paclitaxel before cisplatin, when given as sequential infusions, to limit toxicity. Problems associated with other taxane/platinum combinations are possible, although unsubstantiated. Administering the taxane derivative before the platinum derivative seems prudent.

Erythromycin: Erythromycin may increase the serum levels and toxicity of docetaxel.

Josamycin: Josamycin may increase the serum levels and toxicity of docetaxel.

Ketoconazole: Ketoconazole may increase the serum levels and toxicity of docetaxel.

Midazolam: Midazolam may increase the serum levels and toxicity of docetaxel.

Orphenadrine: Orphenadrine may increase the serum levels and toxicity of docetaxel.

Quinupristin: This combination presents an increased risk of toxicity.

Telithromycin: Telithromycin may reduce clearance of Docetaxel. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Docetaxel if Telithromycin is initiated, discontinued or dose changed.

Testosterone: Testosterone may increase the serum levels and toxicity of docetaxel.

Testosterone Propionate: Testosterone propionate may increase the serum levels and toxicity of docetaxel.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Valrubicin: The taxane derivative, Docetaxel, may increase Valrubicin toxicity. Consider alternate therapy or monitor for toxic effects.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of docetaxel by decreasing its metabolism. Consider using a non-interacting antifungal or monitor for changes in the therapeutic and adverse effects of docetaxel if voriconazole is initiated, discontinued or dose changed.