Docetaxel 114977-28-5
148408-66-6

Chemical structure, nature, and composition

Nature

Docetaxel is of the chemotherapy drug class; taxane, and is a semi-synthetic analogue of paclitaxel (Taxol), an extract from the rare Pacific yew tree Taxus brevifolia. 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. Oral bioavailability has been found to be 8% ±6% on its own and, when co-administered with cyclosporine, bioavailability increased to 90% ± 44%. 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/m² 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. 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 stabilises 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. Compared with mitoxantrone treatment, docetaxel treated patients showed a 12% overall response rate and mitoxantrone showed a 7% overall response rate. Another large advantage of docetaxel was increased quality of life. Docetaxel showed a 22% response and mitoxantrone had a 13% response. Used in conjunction with prednisone for pain management, docetaxel had a 35% response and Mitoxantrone had a 22% response. This trial leads docetaxel to be a preferred method of treatment to Mitoxantrone where possible. is a UK-based six-arm, five-stage, open-label randomized controlled trial involving more than 3000 men. Arm C of this trial involves administering docetaxel in addition to the normal therapy as soon as metastatic prostate cancer has been diagnosed instead of waiting until it has become androgen-independent.

Specific outcomes and benefits of treatment

Treatment with docetaxel has the specific outcome of increasing survival time in patients with certain types of cancer.

Side-effects/contraindications/drug interactions

Adverse side effects

Docetaxel is a chemotherapeutic agent and is a cytotoxic compound and so is effectively a biologically damaging drug. 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 currently protected by patents (U. S. patent 4814470, European patent no EP 253738, due to expire in 2010) which are owned by Sanofi-Aventis, and so is available only under the Taxotere brand name internationally.

Costs

In the UK (in 2009) The cost of 6 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. 75m2).

Clinical Trials

MD Anderson Cancer Center: A phase I/II study of Docetaxel, 5-Fluorouracil and Oxaliplatin (D-FOX) in patients with untreated locally unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction.