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Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. It may be used by itself or along with other chemotherapy medication.
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Common side effects include hair loss, cytopenia (low blood cell counts), numbness, shortness of breath, nausea, vomiting, and muscle pains. Side effects are more common in people with liver problems. It works by disrupting the normal function of microtubules and thereby stopping cell division. It is on the World Health Organization's List of Essential Medicines. Docetaxel is available as a generic medication.
The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule. While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.
Outcomes
Treatment with docetaxel increases survival time in people with certain types of cancer. Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival. Additionally, it has been noted that docetaxel is prone to cellular drug resistance via a variety of different mechanisms.
Monitoring and combination use
Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles.
Side effects
thumb|320px|Incidence of commonly experienced non-haematological adverse effects reported for treatment with docetaxel. Data from 40 phase II and phase III studies (n = 2045) with patients undergoing a one-hour infusion of 100 mg/m<sup>2</sup> docetaxel once every three weeks.
thumb|320px|Incidence of severe adverse effects reported in patients treated with docetaxel. Data from 40 phase II and phase III studies with patients undergoing a one-hour infusion of 100 mg/m<sup>2</sup> docetaxel once every three weeks.
Docetaxel is a cytotoxic chemotherapeutic agent. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as hair loss occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the 'common and frequent' classification. In most cases the primary symptoms is epiphora or tearing. When treated early most patients can avoid the need for surgery, but some cases the only cure is a conjunctivodacryocystorhinostomy in which a glass tube is placed to bypass the tear duct.
Taxane-induced pneumotoxicity is rare. However, 1–5% of patients taking docetaxel may develop severe pneumotoxicity. Patients may develop exertional breathlessness and desaturation which needs to be detected early. Chest X-Ray may show bilateral opacities and High Resolution CT chest may reveal Organizing Pneumonia (OP) pattern or Non-Specific Organizing Pneumonia (NSIP) pattern or a combination. Docetaxel-induced DPLD is a fatal adverse effect, which can be managed by the cessation of the drug and starting on steroids in adequate doses.
As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred. Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent. 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 more readily available leaves of the European yew tree.
Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester, and a tert-butyl carbamate ester exists on the phenylpropionate side chain instead of the benzamide in paclitaxel. The carbon 10 functional group change causes docetaxel to be more water-soluble than paclitaxel. The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. In this T-shaped/butterfly model, a deep hydrophobic cleft exists near the surface of the β-tubulin where three potential hydrogen bonds and multiple hydrophobic contacts bind to docetaxel. The hydrophobic pocket walls contain helices H1, H6, H7 and a loop between H6 and H7 that form hydrophobic interactions with the 3'-benzamido phenyl, 3'-phenyl, and the 2-benzoyl phenyl of docetaxel. 3'-phenyl also has contact with β-sheets B8 and B10. The C-8 methyl of docetaxel has Van der Waals interactions with two residues, Thr-276 and Gln-281 near the C-terminal end of β-tubulin. Docetaxel's O-21 experiences electrostatic attraction to Thr-276 and the C-12 methyl has proximity with Leu-371 on the loop between B9 and B10. In practice, docetaxel is administered intravenously only to increase dose precision. Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100 mg/m<sup>2</sup> dosages given over one-hour infusions every three weeks. Docetaxel's plasma protein binding includes lipoproteins, alpha1 acid glycoprotein and albumin. Alpha1 acid glycoprotein is the most variable of these proteins inter-individually, especially in cancer patients and is therefore the main determinant of docetaxel's plasma binding variability.
The concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model. Increased dose resulted in a linear increase of the area under the concentration-time curve and so it is concluded that dose is directly proportional to plasma concentration. 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). This binding stabilizes microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny. Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel. as well as Docefrez by Sun Pharma Global and Zytax by Zydus. Annual sales of Taxotere in 2010 were €2.122 billion (3.1 billion). The patent expired in 2010.
Docetaxel was developed by Rhône-Poulenc Rorer (now Sanofi-Aventis) following from the discoveries of Pierre Potier at CNRS at Gif-sur-Yvette during his work on improvements to the production of paclitaxel (Taxol) using the local European yew.
Costs
In the UK (in 2009) The cost of six cycles (18 weeks) of docetaxel at a dose of 75 mg/m2 IV every 21 days is £5,262 (based on an average body surface area 1.75 m<sup>2</sup>).