Docetaxel (Taxotere)❤Docetaxel (Taxotere) Price❤Docetaxel (Taxotere)Products

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.

 

According to a 2005 article in the journal drugs, docetaxel 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. However the effectiveness of Docetaxel vs. Paclitaxel and other taxenes is still controversial. Several more recent articles have found "no evidence that regimens containing docetaxel yield greater benefits than those including paclitaxel." Additionally, the optimal scheduling of docetaxel and other taxenes remains unconfirmed. A three-week administration schedule used to be and is still considered effective but new studies are indicating a weekly schedule might be better. A 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule." Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis. Annual sales in 2010 were Euro 2.122 billion ($US 3.1 billion). The patent expired in 2010.

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. 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.

 

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.

 

Therapeutic applications and effects

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. Clinical data has shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, head and neck cancers, and melanoma.

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 calculatedbody surface area);

 

Numbers of patients in each dose regiment and previous treatment state

Dosage

75 mg/m²

100 mg/m²

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. The 75 mg/m² cohort showed an overall response rate of 47% and 9% complete responses. Duration of response and the time to progression (treatment failure) had median values of 34 weeks and 22 weeks, respectively. Patients with two or fewer organs involved had a response rate of 58.6%, whereas patients with three or more organs involved showed 29.4% response.

 

Previously untreated patients in the 100 mg/m² cohort had an overall response rate of 56% and 9.4% complete responses. The previously treated population had an overall response of 48.6% and 3.6% complete responses. Median duration of response and time to progression was 30 weeks and 21 weeks for the previously untreated population and 28 weeks and 19 weeks for the previously treated patients. The 100 mg/m² cohort showed higher toxicity. Previously untreated patients with three or more organs involved had a 54.3% response rate and previously treated patients had a 55.8% response rate.

 

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/m² dosages administered over a one-hour infusion every three weeks for seven and ten cycles respectively. While no significant differences in median time to progression or survival were observed between docetaxel and doxorubicin in alkylating agent failure patients, anthracycline failure patients showed increased response rate to docetaxel. Median time to progression and median overall survival were also improved with docetaxel.

 

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/m² Taxotere every three weeks and paclitaxel as a three-hour infusion of 175 mg/m² 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/m² n=225

Paclitaxel 175 mg/m² 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. Patients treated for non-small cell lung cancer in phase II studies with 100 mg/m² docetaxel showed an overall response rate of 26.9% for previously untreated patients (n=160) and 17% for previously treated patients (n=88).

Metastatic prostate cancer

The TAX 327 trial was a phase III study that showed significant survival benefit from docetaxel in androgen-independent metastaticprostate 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.

 

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.

Specific outcomes and benefits of treatment

Treatment with docetaxel has the specific outcome of increasing survival time in patients with certain types of cancer. While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large. Many patients survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel. Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival. Conjunctive treatment of prednisone with docetaxel has been shown to lead to improved survival rate as well as improved quality of life and reduction of pain compared with treatments with mitoxantrone. Docetaxel has been shown to improve survival as an adjuvant therapy with doxorubicin and cyclophosphamide for the treatment of node-positive breast cancer and so docetaxel has the benefit of aiding other treatments.

 

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. Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice. Docetaxel has also been found to have greater cellular uptake and is retained longer intracellularly than paclitaxel allowing docetaxel treatment to be effective with a smaller dose, leading to fewer and less severe adverse effects.

Adverse effects

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 westFranceare 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 - See more at:

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