Docetaxel (as generic or under the trade name Taxotere) is a clinically well-established anti-mitotic chemotherapy medication (that is, it interferes with cell division). It is used mainly for the treatment of breast, ovarian, prostate, and non-small cell lung cancer. Docetaxel has an FDA approved claim for treatment of patients who have locally advanced, or metastatic breast or non small-cell lung cancer who have undergone anthracycline-based chemotherapy and failed to stop cancer progression or relapsed and a European approval for use in hormone-refractory prostate cancer. Docetaxel is a chemotherapeutic agent and is a cytotoxic compound and so is effectively a biologically damaging drug. As with all chemotherapy, adverse effects are common and many varying side-effects have been documented. Because docetaxel is a cell cycle specific agent, it is cytotoxic to all dividing cells in the body. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as alopecia occur; sometimes this can be permanent. However, the drugs company Sanofi Aventis claim they do not routinely keep this data. North west France are conducting a survey to establish exactly how many patients are being disfigured in this way. Independent studies show it could be as high as 6.3% which puts this ASE in the 'common and frequent' classification. Docetaxel is a clinically well established anti-mitotic chemotherapy medication used mainly for the treatment of breast, ovarian, and non-small cell lung cancer. Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules. Docetaxel is a white powder and is the active ingredient available in 20 mg and 80 mg Taxotere single-dose vials of concentrated anhydrous docetaxel in polysorbate 80. The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. 20 mg Taxotere is distributed in a blister carton containing one single-dose vial of Taxotere (docetaxel) preparation in 0.5 mL sterile pyrogen-free anhydrous polysorbate 80, and a single dose Taxotere solvent vial containing 1.5 mL 13% ethanol in saline to be combined and diluted in a 250 mL infusion bag containing 0.9% sodium chloride or 5% glucose for administration. 80 mg Taxotere is supplied identically but with 2.0 mL polysorbate 80 and 6.0 mL 13% ethanol in saline. The docetaxel and solvent vials are combined to give a solution of 10 mg/mL and the required dose is drawn from this solution. Vials have an overfill to compensate for liquid loss during preparation, foaming, adhesion to vial walls and the dead volume. 20 mg vials may be stored for 24 months below 25 °C away from light and 80 mg vials for 26 months in the same conditions. Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes. Metabolism is principally oxidative and at the tert-butylpropionate side chain, resulting first in an alcohol docetaxel (M2), which is then cyclised to three further metabolites (M1, M3 and M4). M1 and M3 are two diasteromeric hydroxyoxazolidinones and M4 is an oxazolidinedione. Phase II trials of 577 patients showed docetaxel clearance to be related to body surface area and; hepatic enzyme and alpha1 acid glycoprotein, plasma levels. The following model is agreed to represent docetaxel clearance in humans:; Docetaxel is of the chemotherapy drug class; taxane, and is a semi-synthetic analogue of paclitaxel (Taxol), an extract from the bark of the rare Pacific yew tree Taxus brevifolia. Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and readily available European yew tree. Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved. Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies. Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants. STAMPEDE is a UK-based six-arm, five-stage, open-label randomized controlled trial involving more than 3000 men. Arms C and E of this trial involves administering docetaxel in addition to the normal hormone therapy therapy to men starting long-term hormone therapy for the first time. This could be newly diagnosed metastatic, newly diagnosed non-metastatic or high-risk, previously-treated prostate cancer. The trial tests the value of the drug earlier in the treatment pathway instead of waiting until it has become androgen-independent.
Belongs to the class of organic compounds known as taxanes and derivatives. These are diterpenoids with a structure based either on the taxane skeleton, or a derivative thereof. In term of phytochemistry, several derivatives of the taxane skeleton exist: 2(3->20)-Abeotaxane, 3,11-cyclotaxane, 11(15->1),11(10->9)-abeotaxane, 3,8-seco-taxane, and 11(15->1)-abeotaxane, among others. More complex skeletons have been found recently, which include the taxane-derived [3.3.3] Propellane ring system.
