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. active regions a model based on electron crystallographic density and nuclear magnetic resonance deconvolution has been proposed to explain the binding of docetaxel to β-tubulin. 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. pharmacokinetics absorption and distribution 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 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. docetaxel interacted little with erythrocytes and was unaffected by the polysorbate 80 in its storage medium. polysorbate 80 may be the cause of hypersensitivity reasons in taxanes as recent studies indicated. the concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model. an initial, relatively rapid decline, with an α half-life of mean 4.5 minutes is representative of distribution to peripheral compartments from the systemic circulation. a β half-life of mean 38.3 minutes and a relatively slow γ half-life of mean 12.2 hours represent the slow efflux of docetaxel from the peripheral compartment. administration a 100 mg/m2 dose over a one-hour infusion gave a mean total body clearance of 21 l/h/m2 and a mean steady state volume of distribution of 73.8 l/m2 or 123 l based on the mean bsa (body surface area) of 1.68 m2. area under the plasma concentration-time curve had a mean value of 2.8 mg.h/l. the cmax of docetaxel was found to be 4.15 ± 1.35 mg/l. 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 diastereomeric hydroxyoxazolidinones and m4 is an oxazolidinedione. phase ii trials of 577 patients showed docetaxel clearance is related to body surface area and to hepatic enzyme and alpha1 acid glycoprotein plasma levels. the following model represents docetaxel clearance in humans: cl = bsa · (22.1 − 3.55·aag − 0.095·age + 0.2245·alb) · (1 − 0.334·hep12) where cl is total body clearance (l/h), bsa is total body surface area (m2), aag and alb represent alpha1 acid glycoprotein and albumin plasma concentrations (g/l) respectively, and age is the patients age (years). hep12 represents a measure of hepatic dysfunction, affecting clearance of docetaxel. this final model accounted for a modest proportion of patients and identified most of the patients varying from the model (population median of cl = 35.6 l/h) as having hepatic dysfunction, indicating hepatic function as the most unpredictable factor with regards to clearance variability. 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. clearance has been shown from population pharmacokinetic studies to decrease significantly with age, increased alpha1 acid glycoprotein and albumin concentrations and decreased body surface area. renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination. limited data is available for docetaxel use in children with dosage between 55 and 75 mg/m2. two paediatric studies have taken place that show a mean clearance of 33 l/h/m2 and concentration-time profiles best fitted by a two-compartmental model of distribution and elimination. mean distribution half-life was 0.09 hours and mean elimination half-life was 1.4 hours in paediatric studies. biodistribution of 14c-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces. of the radioactively labelled docetaxel administered, 80% was eliminated to the faeces with 5% in the urine over seven days, an indication that urinary excretion of docetaxel is minimal. saliva contributed minimal excretion and no excretion was detected through pulmonary means. the terminal half-life of docetaxel was determined as approximately 86 hours, through prolonged plasma sampling, contrary to the clinically stated terminal half-life of 10–18 hours. mechanism of action 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 stabilizes 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. it has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis-blocking in its oncoprotein form. 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. both in vitro and in vivo analysis show the anti-neoplastic activity of docetaxel to be effective against a wide range of known cancer cells, cooperate with other anti-neoplastic agents activity, and have greater cytotoxicity than paclitaxel, possibly due to its more rapid intracellular uptake. 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. docetaxel does not block disassembly of interphase microtubules and so does not prevent entry into the mitotic cycle, but does block mitosis by inhibiting mitotic spindle assembly. this can lead to mitotic catastrophe. resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel. microtubules formed in the presence of docetaxel are of a larger size than those formed in the presence of paclitaxel, which may result in improved cytotoxic efficacy. abundant formation of microtubules and the prevention of replication caused by docetaxel leads to apoptosis of tumour cells and is the basis of docetaxel use as a cancer treatment. docetaxel activity is significantly greater in ovarian and breast tumours than for lung tumours. society and culture discovery, regulation and marketing docetaxel is marketed worldwide under the name taxotere by sanofi-aventis as well as docefrez by sun pharma global and zytax by zydus. annual sales of taxotere in 2010 were €2.122 billion (us$3.1 billion). the patent expired in 2010. taxotere 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 taxol. 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 m2).