Docetaxel , sold under the trademark Taxotere among others, is a chemotherapy drug used to treat a number of cancers. These include breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small cell lung cancer. It can be used by itself or along with other chemotherapy drugs. This is given by slow injection into the blood vessels.
Common side effects include hair loss, low blood cell count, numbness, shortness of breath, vomiting, and muscle aches. Other severe side effects include allergic reactions and cancer in the future. Side effects are more common in people with liver problems. Use during pregnancy may harm the baby. Docetaxel is in a taxane family of drugs. It works by disrupting the normal functioning of microtubules and thus halting cell division.
Docetaxel was patented in 1986 and approved for medical use in 1995. This is a List of Essential Medicines of the World Health Organization, the most effective and safe drugs needed in the health system. Docetaxel is available as a generic drug. Wholesale costs in developing countries are about US $ 15,53 to US $ 87/37> 80 bottles. This dose in the United Kingdom costs NHS about Ã, Â £ 454,53.
Video Docetaxel
Medical use
Docetaxel is used in the treatment of various types of cancer, including breast, lung, prostate, stomach, head and neck, and ovarian cancer. Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, kidney, stomach, and head and neck cancers and melanoma. In docetaxel hormone-refractory hormone prostate increases life expectancy and overall quality of life.
The optimal dose scheduling of the taxane remains unconfirmed, but most studies find significant death benefits following a three week or weekly administration schedule. While a 2010 article in Clinical Pharmacology today states, "Weekly administration has emerged as an optimal schedule," the official docetaxel package includes recommending administration every three weeks.
Results
Treatment with docetaxel increases survival time in people with certain types of cancer. While some clinical trials show the average survival time to be increased by about three months, the lifespan is large. Many people survive beyond five years with treatment from docetaxel, but it is difficult to link these findings directly to treatment with docetaxel. An increase in survival time and median response indicates that docetaxel slows the development of metastatic cancer and may lead to disease-free survival. Conjunctival treatment of prednisone with docetaxel has been shown to improve survival rates as well as improve quality of life and reduce pain compared with treatment with mitoxantrone.
As well as mitotic inhibitors, the presence of docetaxel has been found to lead to the phosphorylation of bcl-2 oncoprotein, leading to apoptosis of cancer cells that previously blocked the mechanism of apoptotic induction, leading to tumor regression. Increased effects of radiation therapy when combined with docetaxel have been observed in mice. Docetaxel has also been found to have greater cellular uptake and is maintained longer intracellularly than paclitaxel which allows the treatment of docetaxel to be effective with smaller doses, leading to fewer and less severe adverse effects.
Breast cancer
Docetaxel and paclitaxel have comparable metastasis breast cancer benefits but paclitaxel has a milder side effect. In addition, it has been noted that docetaxel is susceptible to cellular drug resistance through a variety of different mechanisms.
Monitoring and combinations with other drugs
Docetaxel is administered by infusion one hour every three weeks for ten or more cycles. Treatment is given under the supervision of an oncologist. Strict monitoring of blood cell count, liver function, serum electrolytes, serum creatinine, cardiac function and fluid retention are needed to track tumor cell growth, response, adverse reactions and toxicity so that treatment can be modified or discontinued if necessary.
Predictions with corticosteroids are recommended before each administration of docetaxel to reduce fluid retention and hypersensitivity reactions. Other drugs are often given to help management of pain and other symptoms. Breast cancer treatment with doxorubicin and cyclophosphamide is enhanced by adjuvant treatment with docetaxel. Docetaxel is also used in combination with capecitabine, a DNA synthesis inhibitor.
Maps Docetaxel
Side effects
Docetaxel is a cytotoxic chemotherapeutic agent. As with all chemotherapy, side effects are common, and many side effects have been documented. Because docetaxel is a specialized agent of the cell cycle, it is cytotoxic to all cells that divide within the body. These include tumor 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. Northwestern France conducted a survey to determine how many people were affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the 'common and frequent' classification.
Hematologic side effects include neutropenia (95.5%), anemia (90.4%), febrile neutropenia (11.0%) and thrombocytopenia (8.0%). Deaths due to toxicity accounted for 1.7% of the 2045 patients, and incidence increased (9.8%) in patients with elevated liver function tests (liver dysfunction).
Severe adverse events observed in phase II studies of the 40th and Phase III were also recorded.
Many side effects have been reported for adjunct and adjuvant treatment with docetaxel and rare post-marketing events.
Contraindications and patient factors
Docetaxel is contraindicated for use with patients with an initial neutrophil count of less than 1500 cells/Ã,ÂμL, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver disorders and pregnant or lactating women.
Side effects are experienced more frequently by patients aged 65 years or older, but doses usually do not decrease. Kidney failure is not considered to be a significant factor for docetaxel dose adjustment. Patients with liver insufficiency result in serum bilirubin greater than the normal upper limit (ULN) should not be given docetaxel, although this is not a contraindication expressed. Dosage should be reduced by 20% in people who develop grade 3 or 4 diarrhea after exposure to docetaxel, defined hepatotoxicity by liver enzymes at levels greater than five times ULN, and palmer-planter grade 2 toxicity.
The pediatric trial of docetaxel has been restricted, so the safety of use in patients under 16 years has not been established.
Pregnancy
Based on limited data available, docetaxel appears to be safe in pregnancy if given during the second and third trimesters; However, the risks of mother and fetus should be weighed against the benefits of determining the right course of action. Like all chemotherapy agents, docetaxel given to pregnant animals causes a variety of embryofetal toxicities, including death, when administered during the period of organogenesis. However, adequate research investigating the effects of mothers and fetuses on humans is lacking. A small systematic review examining the use of taxanes to treat breast cancer in pregnancy shows that, out of 19 patients, only three congenital malformations occurred. Two cases of cerebral ventriculomegaly observed in the study were documented prior to administration of chemotherapy, suggesting an alternative cause of congenital malformations. The third case involves pyloric stenosis in infants whose mothers receive a combination of docetaxel, doxorubicin, cyclophosphamide and paclitaxel regimens; because the fetus is exposed to many drugs in the womb, it remains difficult to identify docetaxel as a cause teratogenic agent. More research is needed to better assess the safety of docetaxel in pregnancy and determine the right dose in pregnant women.
Drug interactions
Drug interactions can be caused by pharmacokinetic or pharmacodynamic changes due to one of the drugs involved. Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine were all potentially administered with docetaxel and did not modify the binding docetaxel plasma in phase II studies. Cisplatin is known to have complex interactions with some CYPs and in some instances has been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A showed increased expression in response to anticonvulsant use and metabolism of docetaxel M4 metabolites processed by these CYPs. An appropriate increase in M4 clearance by 25% was observed in patients taking phenytoin and phenobarbital, common anticonvulsants.
Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel. When used with anticonvulsants, which induce CYP3A4, increased dose of docetaxel may be necessary.
Pre-treatment with corticosteroids has been used to reduce hypersensitivity and edema reactions in response to docetaxel and did not show any effect on docetaxel pharmacokinetics. The efficacy of docetaxel is enhanced by treatment with oral capecitabine, and after more than 27 months of follow-up, survival benefits have been confirmed. Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an AUC increase of docetaxel of 50 to 70%, suggesting doxorubicin may affect the docetaxel disposition. Etoposide has also been shown to decrease the permit docetaxel, although the number of patients for this observation is low.
Prednisone administered with docetaxel leads to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.
Chemistry
Docetaxel is a class of chemotherapy drugs; taxane, and is a semi-synthetic analog of paclitaxel (Taxol), extract from rare bark of Pacific yew Taxus brevifolia. Due to the scarcity of paclitaxel, extensive research was conducted leading to the docetaxel formulation - esterified product of 10-deacetyl baccatin III, extracted from European renewable yew leaf and more readily available.
Docetaxel differs from paclitaxel in two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has acetic esters, and tert-butyl carbamate esters are present on the phenylpropionate side chain instead of benzamide in paclitaxel. The change in the carbon-functional group causes docetaxel to become more water soluble than paclitaxel.
Formulation and composition
Docetaxel is a white powder and is an active ingredient available in 20% mg and 80 mg Taxotere single-dose vial of a concentrated anhydrous docetaxel in polysorbate 80. The solution is clear chocolate containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. 20mg Taxotere distributed in blister cartons containing one single dose of Taxotere dose (docetaxel) preparation at 0.5 mL sterile free pyrogen free polysorbate 80, and sole solvent taxotere dose containing 1.5 mL 13% ethanol in salt to be combined and diluted in 250 mL infusion pouch containing 0.9% sodium chloride or 5% glucose for administration. 80mg Taxotere is given identically but with 2.0 mL polysorbate 80 and 6.0 mL of 13% ethanol in the salt. Docetaxel and solvent solutions were combined to give 10 mg/mL solution and the required dose was taken from this solution. The bottle has excess filling to compensate for fluid loss during preparation, foaming, adhesion to the vial wall and dead volume. 20 mg vial can be stored for 24 months under 25 Â ° C away from light and 80 mg vial for 26 months under the same conditions.
Recently Sanofi has received approval for a bottle formulation. With this one bottle formulation, the preparation of the infusion solution is simplified by eliminating the first dilution step. The formulation of two bottles and one bottle contains the same drug, docetaxel trihydrate, and the same excipient (ethanol, polysorbate 80 and citric acid). A one-bottle formulation is provided as an aqueous intravenous solution containing the same drug in the same concentration as an approved two-bottle formulation. The same quality, 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 region
A model based on electron crystal 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 some hydrophobic contact bind to docetaxel. The hydrophobic pocket wall contains H1, H6, H7 and H6 loops between H6 and H7 which form hydrophobic interactions with phenyl 3'-benzamido, 3'-phenyl, and 2-benzoyl phenyl from docetaxel. 3'-phenyl also have contact with? -sheets B8 and B10. Methyl C-8 from docetaxel has Van der Waals interactions with two residues, Thr-276 and Gln-281 near the terminals of the C-terminal of -tubulin. O-21 Docetaxel undergoes electrostatic attraction to Thr-276 and methyl C-12 has proximity to Leu-371 on the loop between B9 and B10.
Pharmacokinetics
Absorption and distribution
Oral bioavailability has been found to be 8% Ã,  ± 6% alone and, when administered together with cyclosporine, bioavailability increased to 90% Ã,  ± 44%. In practice, docetaxel is given intravenously only to improve the accuracy of the dosage. Pharmacokinetic evaluation of docetaxel in phase II and III clinical studies was at a dose of 100 mg/mÃ,² administered for one hour infusion every three weeks.
Docetaxel proved to be greater than 98% plasma proteins binding to concentrations at 37 ° C and pH 7.4 binding to Docetaxel plasma proteins including lipoproteins, alpha1 glycoprotein and albumin. Alpha1 acid glycoproteins are the most variable of these inter-individual proteins, especially in cancer patients and therefore a major determinant of docetaxel plasma binding variability. Docetaxel slightly interacts with erythrocytes and is not affected by polysorbate 80 in its storage media. Polysorbate 80 may be the cause of hypersensitivity reasons in taxanes as indicated by recent studies.
The time-concentration profile of docetaxel is consistent with the pharmacokinetic model of the three compartments. Early decline, relatively fast, with? the average half-life of 4.5 minutes is representative of the distribution to the peripheral compartment of the systemic circulation. A? the average half-time is 38.3 minutes and relatively slow? the average half-life of 12.2 hours is a gradual slowdown of the docetaxel of the peripheral compartment.
A dose of 100mg/mÃ,² for an hour of infusion gave a mean total body of 21 L/h/mÃ,² and a steady distribution volume average of 73.8 L/mÃ,² or 123 L based on BSA average ( surface area) area of ​​1.68 mÃ,². The area under the plasma concentration-time curve has an average value of 2.8 mg/hr. Cmax of docetaxel was found to be 4.15  ± 1.35 mg/L. Increased doses resulted in a linear increase of the area under the time-concentration curve and so it was concluded that the dose was directly proportional to the plasma concentration.
Metabolism and excretion
Docetaxel is primarily metabolized in the liver by cytochrome P450 CYP3A4 and CYP3A5 subfamilies isoenzymes. Metabolism is essentially oxidative and on the tert-butylpropionate side chain, producing first in docetaxel alcohol (M2), which is then cyclized to three further metabolites (M1, M3 and M4). M1 and M3 are the two hydroxyocalzolidinone diastereomers and M4 is oxazolidinedione. Phase II trial of 577 patients showed docetaxel clearance associated with body surface area and for liver enzyme and alpha glycoprotein plasma level. The following model demonstrates the permission of docetaxel in humans:
where CL is total body clearance (L/h), BSA is total body surface area (m²), AAG and ALB represent alpha1 acid glycoprotein and plasma albumin (g/L) concentration respectively, and AGE is patient age (years). HEP12 is a measure of liver dysfunction, which affects the cleaning of docetaxel. This final model contributes to a modest proportion of patients and identifies the majority of patients who vary from model (median population CL = 35.6 L/h) as having liver dysfunction, indicating liver function as the most unpredictable factor with regard to clearance variability.
Patients with significant liver dysfunction experienced a 30% decrease in docetaxel removal and also high risk of toxicity poisoning from docetaxel treatment. Clearance has been demonstrated from population pharmacokinetic studies to decrease significantly with age, increased alpha1 acid glycoprotein and albumin concentration and decreased body surface area.
Kidney damage is unlikely to affect the metabolism or excretion of docetaxel because renal excretion accounts for less than 5% elimination. Limited data is available for docetaxel use in children with doses between 55 and 75Ã, mg/mÃ,². Two pediatric studies have been performed showing an average opening of 33 L/hr/m² and the best time-concentration profiles installed by the distribution model and the elimination of two compartments. The average half-life of the distribution was 0.09 hours and the mean half-life of elimination was 1.4 hours in pediatric studies.
Biodistribusi doketaxel labeled 14C in three patients showed most drugs were metabolized and excreted in bile to faeces. From the labeled radioactive labeled docetaxel, 80% was eliminated into the feces by 5% in urine for seven days, an indication that urine docetaxel excretion was minimal. Saliva contributes minimal excretion and no excretion is detected through the lungs. The term half-life of docetaxel is determined about 86 hours, via prolonged plasma sampling, in contrast to the clinically stated terminal terminal of 10-18 hours.
Action mechanism
Molecular targets
Docetaxel binds microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole of docetaxel per mole of tubulin in microtubules. This bond stabilizes microtubules and prevents depolymerization of calcium ions, decreased temperature and dilution, especially at the tip plus microtubules. Docetaxel has been found to accumulate into higher concentrations in ovarian adenocarcinoma cells rather than renal carcinoma cells, which may contribute to the treatment of ovarian cancer more effectively by docetaxel. It has also been found to lead to the phosphorylation of bcl-2 oncoprotein, which is blocking apoptosis in its oncoprotein form.
Action mode
The cytotoxic activity of docetaxel is given by promoting and stabilizing the microtubule assembly, while preventing physiological microtubule depolymerization/dismantling in the absence of GTP. This leads to a significant reduction in free tubulin, required for microtubular formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further offspring of cancer cells.
Because microtubules do not disassemble in the presence of docetaxel, microtubules accumulate in cells and cause initiation of apoptosis. Apoptosis is also driven by blocking apoptosis-blocking bcl-2 oncoprotein. Both in vitro and in vivo analysis show the anti-neoplastic activity of docetaxel to be effective against known cancer cells, in association with the activity of other anti-neoplastic agents, and have cytotoxicity greater than paclitaxel, probably due to its faster intracellular absorption.
The main mode of docetaxel therapeutic action is the suppression of microtubule dynamic assembly and disassembly, rather than bundling microtubules leading to apoptosis, or blocking bcl-2.
Mobile response
Docetaxel shows cytotoxic activity in the breast, colorectal, lung, ovary, stomach, kidney and prostate cancer cells. Docetaxel does not block the dismantling of interphase microtubules and does not prevent entry into the mitotic cycle, but it blocks mitosis by inhibiting the assembly of the mitotic spindle. Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel. The microtubules formed in the presence of docetaxel have a larger size than those formed in the presence of paclitaxel, which can result in increased cytotoxic efficacy. The excessive formation of microtubules and the prevention of replication caused by the presence of docetaxel cause tumor cell apoptosis and is the basis for the use of docetaxel as a cancer treatment. It is not known whether pathophysiological interactions with docetaxel exist at this stage, but tumor types have been shown to have efficacy in cellular activity. Docetaxel activity is significantly greater in ovarian and breast tumors than lung tumors.
Society and culture
Discovery, setting and marketing
Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis and Docefrez by Sun Pharma Global and Zytax by Zydus. Taxotere's annual sales in 2010 were EUR2.122 billion ( US $ 3.1 billion). The patent expires in 2010.
Taxotere was developed by RhÃÆ'Â'ne-Poulenc Rorer (now Sanofi-Aventis) following the discovery of Pierre Potier on CNRS at Gif-sur-Yvette during his work on increasing Taxol production.
Cost
In the UK (in 2009) The six cycle (18 weeks) cost of docetaxel at a dose of 75 mg/m2 IV every 21 days was Ã, Â £ 5,262 (based on average body surface area 1.75 m 2 ).
See also
References
External links
![Full text] Docetaxel-loaded solid lipid nanoparticles suppress ...](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_tJMrmTPKrABFCqJoPwVAbgZcS2Q1FQRh4AqnClG0PPnwHMtPA4G_8UGzOT2tNcIz49NZzA1y4ZEpSJwriP7l2rcmJulv0eNTYyTRYIaogCnpxdAaO6Juou4Oc5waKvogOAHM1ThQqkqA=s0-d "Full text] Docetaxel-loaded solid lipid nanoparticles suppress ...")
Source of the article : Wikipedia
0 Comments