Docetaxel (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, and non-small cell lung cancer.

Administered as a one-hour infusion every three weeks generally over a ten cycle course, docetaxel is considered as or more effective than doxorubicin, paclitaxel and fluorouracil as a cytotoxic antimicrotubule agent. Annual sales approx $2bn. Patent expires in 2010.

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. 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.

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 benzyl amide in paclitaxel. The carbon 10 functional group change causes docetaxel to be more water soluble than paclitaxel.

Formulations and compositions

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.

Recently Sanofi has got approval for one-vial formulation. With this one-vial formulation, the preparation of the infusion solution is simplified by eliminating the first dilution step.

The two-vial and one-vial formulations contain the same drug substance, docetaxel trihydrate, and the same excipients (ethanol, polysorbate 80 and citric acid).

The one-vial formulation is administered as an aqueous intravenous solution that contains the same drug substance in the same concentration as the already approved two-vial formulation. The same grade, quality, and quantity of polysorbate 80 are present in the infusion solution of both formulations. The only difference between these two formulations is the quantity of ethanol.

Active regions

A model based on electron crystallographic density and nuclear magnetic resonance deconvolution has been proposed to explain the binding of docetaxel to ??-tubulin . In this T-shaped/butterfly model, a deep hydrophobic cleft exists near the surface of the ??-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 ??-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 ??-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.

Absorption and distribution

Intravenous administration of docetaxel results in 100% bioavailability and absorption is immediate. Oral bioavailability has been found to be 8% ??6% on its own and, when co-administered with cyclosporine, bioavailability increased to 90% ?? 44%. Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100 mg/m?? dosages given over one-hour infusions every three weeks..

Docetaxel was shown to be greater than 98% plasma protein bound independent of concentration at 37??C and pH 7.4 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.

Administration a 100 mg/m?? dose over a one hour infusion gave a mean total body clearance of 21 L/h/m?? and a mean steady state volume of distribution of 73.8 L/m?? or 123 L based on the mean BSA ( body surface area) of 1.68 m??. 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 and excretion

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:

where CL is total body clearance (L/h), BSA is total body surface area (m??), AAG and ALB represent alpha1 acid glycoprotein and albumin plasma concentrations (g/L) respectively, and AGE is the patients age (years).

Patients with significant hepatic dysfunction had an approximately 30% decrease in clearance of docetaxel and were also at a higher risk of toxicity poisoning from docetaxel treatment.

Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination.

Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces.

Molecular target

Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules. This binding stabilises microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule. Docetaxel has been found to accumulate to higher concentration in ovarian adenocarcinoma cells than kidney carcinoma cells, which may contribute to the more effective treatment of ovarian cancer by docetaxel.

Modes of action

The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP . 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.

Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein.

The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly, rather than microtubule bundling leading to apoptosis, or the blocking of bcl-2.

Cellular responses

Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.

Therapeutic applications

The main use of docetaxel is the treatment of a variety of cancers after the failure of anthracycline-based chemotherapy. Marketing of docetaxel as Taxotere is mainly towards the treatment of breast, prostate and other non-small cell cancers.

Breast cancer

In the treatment of breast cancer, eight phase II studies were carried out in patients with either locally advanced or metastatic breast cancer. A total of 283 previously untreated and treated patients underwent the following dose allocations (dosing based on calculated body surface area);

Numbers of patients in each dose regiment and previous treatment state

Dosage	75 mg/m??	100 mg/m??	Total
Previously Untreated	55	117	172
Previously Treated	-	111	111
			'''283

Taxotere was administered over a one-hour infusion every three weeks for these trials.

Previously untreated patients in the 100 mg/m?? cohort had an overall response rate of 56% and 9.4% complete responses.

Two randomised phase III studies of 326 alkylating agent failure and 392 anthracycline failure metastatic breast cancer patients have been carried out with 100 mg/m?? dosages administered over a one-hour infusion every three weeks for seven and ten cycles respectively.

The following table is the results of an unpublished, non-peer reviewed , comparative, open-label, randomised phase III study of docetaxel and paclitaxel assigned randomly to 449 patients with advanced breast cancer. Docetaxel was administered as a one-hour infusion of 100 mg/m?? Taxotere every three weeks and paclitaxel as a three-hour infusion of 175 mg/m?? paclitaxel every three weeks.

Results of an open-label, multicentre, randomised phase III study in 449 advanced breast cancer patients, comparing efficacy of docetaxel and paclitaxel

Endpoint	Docetaxel 100 mg/m?? n=225	Paclitaxel 175 mg/m?? n=224	p-value
Median survival (months)	15.3	12.7	0.03
Median time to progression (weeks)	24.6	15.6	<0.01
Overall response rate (%)	32.0	25.0	0.10
Overall response rate in evaluable population (%)	37.0	26.0	0.01

Lung cancer

Clinical studies have taken place for the treatment of non-small cell lung cancer.

Metastatic prostate cancer

The TAX 327 trial was a phase III study that showed significant survival benefit from docetaxel in androgen-independent metastatic prostate cancer. 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. Subsequently EU approval.

Specific outcomes and benefits of treatment

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

As well as inhibiting mitosis, the presence of docetaxel has been found to lead to the phosphorylation of the oncoprotein bcl-2, which leads to apoptosis of cancer cells that had previously blocked the apoptotic inducing mechanism, leading to tumour regression.

Monitoring and combination with other drugs

Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles.

Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions.

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. Independant study's show it could be as high as 6.3% which puts this ASE in the 'common and frequent' classification.

Haematological adverse effects include Neutropenia (95.5%), Anaemia (90.4%), Febrile neutropenia (11.0%) and Thrombocytopenia (8.0%).

Observations of severe side effects in the above 40 phase II and phase III studies were also recorded.

Many more side effects have been reported for conjunctive and adjuvant treatment with docetaxel as well as rare post-marketing events.

Contraindications and patient factors

Docetaxel is contraindicated for use with patients with; a baseline neutrophil count less than 1500 cells/??L, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.

Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased.

Paediatric trials of docetaxel have been limited and so safety of use in patients under 16 years has not been established.

Drug interactions

Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved.

Common and/or likely drug-drug combinations and known side effects from drug interactions

Drug Interacting with Docetaxel	Adverse Effects from Interaction
Cisplatin	increased risk of delayed neuropathy
Cyclosporine, Dalfopristin, Erythromycin, Itraconazole, Ketoconazole, Quinupristin, Terfenadine, Troleandomycin	increased risk of docetaxel toxicity including some or all of; anaemia, leucopoenia, thrombocytopenia, fever, diarrhoea
Doxorubicin Hydrochloride	cholestatic jaundice and pseudomembranous colitis
Doxorubicin Hydrochloride Liposome	increased doxorubicin exposure
Vaccinations for; Bacillus of Calmette and Guerin, Measles, Mumps, Poliovirus, Rotavirus, Rubella, Smallpox, Typhoid, Varicella, Yellow Fever	increased risk of infection by live vaccine
Thalidomide	increased risk of venous thromboembolism

Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel.

Pre-treatment with corticosteroids has been used to decrease hypersensitivity reactions and oedema in response to docetaxel and has shown no effect on the pharmacokinetics of docetaxel.

Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.

Taxotere was developed by Rh??ne-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 Taxol.

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).

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.

• Exudative hyponychial dermatitis

• Scleroderma-like reaction to taxanes

• Taxotere (manufacturer's prescribing information)

• Taxotere (manufacturer's website)