Docetaxel

Docetaxel is a clinically well established anti-mitotic chemotherapy medication used mainly for the treatment of breast, ovarian, and non-small cell lung cancer.^[1][2] Docetaxel has an 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.^[3] Administered as a one-hour infusion every three weeks generally over a ten cycle course, docetaxel is considered better than doxorubicin, paclitaxel and fluorouracil as a cytotoxic antimicrotubule agent.^[1] Docetaxel is marketed under the name Taxotere by Sanofi-Aventis U.S. LLC.^[4]

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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.^[2] 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 substitution exists on the phenylpropionate side chain. The carbon 10 functional group change causes docetaxel to be more lipid soluble than paclitaxel.^[2]

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.^[5][2] The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL.^[5] 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.^[5] 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.^[5]

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.^[6] 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 Waal's 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.^[6]

Pharmacokinetics

Absorption and distribution

Intravenous administration of docetaxel results in 100% bioavailability and absorption is immediate.^[7] Oral bioavailability has been found to be 8% ±6% on its own and when co-administered with cyclosporine, bioavailability increased to 90% ± 44%.^[8] In practice, docetaxel is administered intravenously only to increase dose precession.^{[2][5][9][10]} 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.^[2] 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.^[11] Docetaxel interacted little with erythrocytes and was unaffected by the polysorbate 80 in its storage medium.^[2][11]

The concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model.^[2][5] 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.^[2][5]

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.^[2][5] Area under the plasma concentration-time curve had a mean value of 2.8 mg.h/L.^[2] The Cmax of docetaxel was found to be 4.15 ± 1.35 mg/L.^[12] 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.^[2]

Metabolism and excretion

Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes.^[2][13][14] 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).^[14] 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.^[11] The following model is agreed to represent docetaxel clearance in humans:

where CL is total body clearance (L/h), AAG and ALB represent alpha1 acid glycoprotein and albumin plasma concentrations (g/L) respectively, BSA is total body surface area (m²) and AGE is the patients age (years).^[2] 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.^[2]

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.^[2] 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.^[2]

Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination.^[2] 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.^[2]

Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces.^[2] 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.^[2] 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.^[8][12]

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.^[15] This binding stabilises microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule.^[15] 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.^[1][15] It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis blocking in its oncoprotein form.^[1]

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.^[1][16][17] 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.^[1][5][15]

Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis.^[15] Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein.^[1] 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.^[1]

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.^[1][15]

Cellular responses

Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.^[1] 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.^[15] Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel.^[1] 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.^[17] Abundant formation of microtubules and the prevention to replicate caused by the presence of docetaxel leads to apoptosis of tumour cells and is the basis of docetaxel use as a cancer treatment.^[17] It is unknown if pathophysiological interactions with docetaxel exist at this stage, however tumour type has been shown to have efficacy on cellular activity.^[1] Docetaxel activity is significantly greater in ovarian and breast tumours than for lung tumours.^[1]

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.^[3] Marketing of docetaxel as Taxotere® is mainly towards the treatment of breast, prostate and other non-small cell cancers.^[4] Clinical data has shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal and gastric cancer and melanoma cells.^[1][5]

In the treatment of breast cancer, eight phase II studies were carried out in patients with either locally advanced or metastatic breast cancer.^[5] A total of 283 previously untreated and treated patients underwent the following dose allocations;

Taxotere® was administered over a one-hour infusion every three weeks for these trials.^[5] 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.^[5]

Previously untreated patients in the 100 mg/m² cohort had an overall response rate of 56% and 9.4% complete responses.^[5] 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.^[5]

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.^[5] 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.^[5]

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.^[5] 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.

Clinical studies have taken place for the treatment of non-small cell lung cancer and prostate cancer.^[5] 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). Median survival time for previously untreated patients was nine months and for previously treated patients, eight months.^[5]

The TAX 327 trial was a phase III study that showed significant survival benefit from docetaxel in androgen-independent metastatic prostate cancer.^[18] 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.^[18]

Specific outcomes and benefits of treatment

Treatment with docetaxel has the specific outcome of increasing survival time in patients with certain types of cancer.^[1][2][4][5] While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large.^[5] Many patients survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel.^[18] Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival.^[5][9][18] 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.^[18] 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.^[5]

Monitoring and combination with other drugs

Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles.^[5] Treatment is given under supervision from an oncologist and takes place in a hospital, where vital signs are monitored during infusion. Strict monitoring of blood cell counts, liver function, serum electrolytes, serum creatinine, heart function and fluid retention is required to track the progression of tumour cells, response, adverse reactions and toxicity so that treatment can be modified or terminated if necessary.^[5][8]

Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions.^[5] Oral dexamethasone is given before docetaxel treatment for prostate cancer. Docetaxel is typically used for the treatment of carcinoma on its own. Other medications will often be given to aid pain management and other symptoms. The treatment of breast cancer with doxorubicin and cyclophosphamide is enhanced by adjuvant treatment with docetaxel. Docetaxel is also used in combination with capecitabine, a DNA synthesis inhibitor.^[5][19]

Side-effects/contraindications/drug interactions

Positive side-effects

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.^[1] Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice.^[1] 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.^[17]

Adverse effects

Docetaxel is a chemotherapeutic agent and is a cytotoxic compound and so is effectively a biologically damaging drug.^[1][13] As with all chemotherapy, adverse effects are common and many varying side-effects have been documented.^[5][9] Because docetaxel is a cell cycle specific agent, it is cytotoxic to all dividing cells in the body.^[20] 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.^[20]

Haematological adverse effects include Neutropenia (95.5%), Anaemia (90.4%), Febrile neutropenia (11.0%) and Thrombocytopenia (8.0%).^[5][9] Deaths due to toxicity accounted for 1.7% of the 2045 patients and incidence was increased (9.8%) in patients with elevated baseline liver function tests (liver dysfunction).^[5][9]

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.^[5]

Contraindications and patient factors

Docetaxel is contraindicated for use with patients with; a baseline neutrophil count less than 1.5x109 cells/L, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.^[5][9]

Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased.^[5][8] Renal failure is thought not to be a significant factor for docetaxel dosage adjustment.^[8] Patients with hepatic insufficiency resulting in serum bilirubin greater than the upper limit of normal (ULN) should not be administered docetaxel, though this is not a stated contraindication. Dosage should be reduced by 20% in patients who suffer from; grade 3 or 4 diarrhoea following exposure to docetaxel, hepatotoxicity defined by liver enzymes at levels greater than five times the ULN, and grade 2 palmer-planter toxicity.^[8]

Paediatric trials of docetaxel have been limited and so safety of use in patients under 16 years has not been established.^[2][8]

Drug interactions

Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved.^[2] Cisplatin, dexamethasone, doxorubicin, etoposide and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies.^[11] Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%.^[2] Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants.^[2]

Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel.^[2] When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.^[2]

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.^[2] The efficacy of docetaxel was improved by treatment with oral capecitabine and after more than 27 months follow-up, the survival benefit has been confirmed.^[1] Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an increased AUC of docetaxel by 50 to 70%, indicating doxorubicin may affect the disposition of docetaxel.^[2] Etoposide has also been shown to decrease docetaxel clearance, thought patient numbers for this observation have been low.^[2]

Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.^[18]

Discovery, Regulation and Marketing

Taxotere was developed by Rhône-Poulenc Rorer (now Aventis) following from the discoveries of Pierre Potier at CNRS at Gif-sur-Yvette during his work on improvements to the production of Taxol.^[21]

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.^[22]

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.

References