Docetaxel
2235616
220288770
2008-06-19T03:38:50Z
61.11.51.130
{{drugbox
| IUPAC_name = (2''R'',3''S'')-''N''-carboxy-3-phenylisoserine, ''N''-tert-butyl ester, 13-ester with 5, 20-epoxy-1, 2, 4, 7, 10, 13-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate
| image = Docetaxel.svg
| width = 220
| image2 = Docetaxel_Taxotere.gif
| width2= 155
| CAS_number = 114977-28-5
| ATC_prefix = L01
| ATC_suffix = CD02
| ATC_supplemental =
| PubChem = 148124
| DrugBank = APRD00932
| C = 43 | H = 53 | N = 1 | O = 14
| molecular_weight = 807.879 g/mol
| bioavailability = NA
| protein_bound = >98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 86 hours
| excretion = [[Bile|Biliary]]
| pregnancy_category =
| legal_status =
| routes_of_administration = [[Intravenous therapy|IV]] }}
<!-- FAIR USE of Docetaxel_Taxotere.gif: see image description page at<ref name="http://en.wikipedia.org/wiki/Image:Docetaxel_Taxotere.gif">[http://en.wikipedia.org/wiki/Image:Docetaxel_Taxotere.gif http://en.wikipedia.org/wiki/Image:Docetaxel Taxotere.gif]</ref> for rationale -->
'''Docetaxel''' is a clinically well established [[mitotic inhibitor|anti-mitotic]] [[chemotherapy]] medication used mainly for the treatment of breast, ovarian, and non-small cell lung [[cancer]].<ref name="Lyseng-Williamson">Lyseng-Williamson KA, Fenton C. Docetaxel: a review of its use in metastatic breast cancer. Drugs 2005;65(17):2513-31.</ref><ref name="Clarke">Clarke SJ, Rivory LP. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 1999;36(2):99-114</ref> 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.<ref name="FDA">Anonymous. Oncology Tools: Approved Claims for microtubule inhibitors. US Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/onctools/classlist.cfm?Class=microtubule%20inhibitor (17 Sep 2006). Last modified 22 Jun 1998.</ref> 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.<ref name="Lyseng-Williamson"/> Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis.<ref name="Taxotere.comAbout">Anonymous. Taxotere.com for Healthcare Professionals: About. Sanofi-aventis U.S. LLC. http://www.taxotere.com/professional/about/index.do (17 Sep 2006). Last modified Jul 2005.</ref>
==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]].<ref name="Clarke"/> 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 water soluble than paclitaxel.<ref name="Clarke"/>
===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]].<ref name="MedSafe">Anonymous. Taxotere Docetaxel concentrate for infusion. Medsafe. http://www.medsafe.govt.nz/profs/Datasheet/t/taxotereinf.htm (25 Sep 2006). Last modified 6 Feb 2006.</ref><ref name="Clarke"/> The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL.<ref name="MedSafe"/> 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.<ref name="MedSafe"/> 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.<ref name="MedSafe"/>
===Active regions===
A model based on [[crystallography|electron crystallographic]] density and [[nuclear magnetic resonance]] deconvolution has been proposed to explain the binding of docetaxel to [[tubulin|β-tubulin]].<ref name="Snyder">Snyder JP, Nettles JH, Cornett B, Downing KH, Nogales E. The binding conformation of Taxol in b-tubulin: A model based on electron crystallographic density. PNAS. 2001;98(9):5312-16.</ref> 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' forces|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.<ref name="Snyder"/>
==Pharmacokinetics==
===Absorption and distribution===
Intravenous administration of docetaxel results in 100% [[bioavailability]] and absorption is immediate.<ref>Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. London: Churchill Livingstone; 2003. p. 100-1</ref> Oral bioavailability has been found to be 8% ±6% on its own and when co-administered with [[cyclosporine]], bioavailability increased to 90% ± 44%.<ref name="DrugDex">Anonymous. Drugdex Evaluations: Docetaxel. Thomson MICROMEDEX. http://www.library.auckland.ac.nz/databases/learn_database/public.asp?record=micromedex#Drugdex (26 Sep 2006). Last modified 2006.</ref> In practice, docetaxel is administered intravenously only to increase dose precision.<ref name="Clarke"/><ref name="MedSafe"/><ref name="Taxotere.comSafety">Anonymous. Taxotere.com for Healthcare Professionals: Efficacy and Safety. Sanofi-aventis U.S. LLC. http://www.taxotere.com/professional/about/efficacy_safety.do (24 Sep 2006). Last modified Jul 2005.</ref><ref name="Pharmac">Anonymous. New Zealand Pharmaceutical Schedule. Wellington: PHARMAC; 2006. p. 133.</ref> 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.<ref name="Clarke">.
Docetaxel was shown to be greater than 98% plasma protein bound independent of concentration at 37°C and pH 7.4<ref name="Urien">Urien S, Barre J, Morin C, Paccaly A, Montay G, Tillement JP. Docetaxel serum protein binding with high affinity to alpha 1-acid glycoprotein. Invest New Drugs. 1996;14(2):147-51.</ref> 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.<ref name="Urien">Urien S, Barre J, Morin C, Paccaly A, Montay G, Tillement JP. Docetaxel serum protein binding with high affinity to alpha 1-acid glycoprotein. Invest New Drugs. 1996;14(2):147-51.</ref> Docetaxel interacted little with [[erythrocyte]]s and was unaffected by the polysorbate 80 in its storage medium.<ref name="Clarke"/><ref name="Urien"/>
The concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model.<ref name="Clarke"/><ref name="MedSafe"/> An initial, relatively rapid decline, with an α [[Biological half-life|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.<ref name="Clarke"/><ref name="MedSafe"/>
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.<ref name="Clarke"/><ref name="MedSafe"/> [[Area under the curve|Area under the plasma concentration-time curve]] had a mean value of 2.8 mg.h/L.<ref name="Clarke"/> The Cmax of docetaxel was found to be 4.15 ± 1.35 mg/L.<ref name="Baker">Baker SD, Zhao M, Lee CKK, Verweij J, Zabelina Y, Brahmer JR, et al. Comparative pharmacokinetics of weekly and every-three-weeks docetaxel. Clin Cancer Res. 2004;10(6):1976-83.</ref> 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.<ref name="Clarke"/>
===Metabolism and excretion===
Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes.<ref name="Clarke"/><ref name="Taxotere.comPharmacokinetics">Anonymous. Taxotere.com for Healthcare Professionals: Pharmacokinetics. Sanofi-aventis U.S. LLC. http://www.taxotere.com/professional/about/pharmacokinetics.do (23 Sep 2006). Last modified Jul 2005.</ref><ref name="Guitton">Guitton J, Cohen S, Tranchand B, Vignal B, Droz JP, Guillaumont M, et al. Quantification of docetaxel and its main metabolites in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2005;19(17):2419-26.</ref> 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).<ref name="Guitton"/> 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.<ref name="Urien"/> The following model is agreed to represent docetaxel clearance in humans:
<div style='text-align: center;'>'''CL = BSA (22.1 – 3.55AAG – 0.095AGE + 0.2245ALB) . (1 – 0.334HEP12)'''</div>
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).<ref name="Clarke"/> 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.<ref name="Clarke"/>
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.<ref name="Clarke"/> 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.<ref name="Clarke"/>
Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination.<ref name="Clarke"/> 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.<ref name="Clarke"/>
Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces.<ref name="Clarke"/> 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.<ref name="Clarke"/> 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.<ref name="DrugDex"/><ref name="Baker"/>
==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.<ref name="Yvon">Yvon AC, Wadsworth P, Jordan MA. Taxol Suppresses Dynamics of Individual Microtubules in Living Human Tumor Cells. The American Society for Cell Biology. 1999;10:947-959.</ref> This binding stabilises microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule.<ref name="Yvon"/> 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.<ref name="Lyseng-Williamson"/><ref name="Yvon"/> It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis blocking in its oncoprotein form.<ref name="Lyseng-Williamson"/>
===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.<ref name="Lyseng-Williamson"/><ref name="RxListCP">Anonymous. Docetaxel: Clinical Pharmacology. RxList. http://www.rxlist.com/cgi/generic3/docetaxel_cp.htm (24 Sep 2006). Last modified 29 Jun 2006.</ref><ref name="Eisenhauer">Eisenhauer EA, Vermorken JB. The taxoids: Comparative clinical pharmacology and therapeutic potential. Drugs. 1998;55(1):5-30.</ref> 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.<ref name="Lyseng-Williamson"/><ref name="MedSafe"/><ref name="Yvon"/>
Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis.<ref name="Yvon"/> Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein.<ref name="Lyseng-Williamson"/> 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.<ref name="Lyseng-Williamson"/>
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.<ref name="Lyseng-Williamson"/><ref name="Yvon"/>
===Cellular responses===
Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.<ref name="Lyseng-Williamson"/> 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.<ref name="Yvon"/> Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel.<ref name="Lyseng-Williamson"/> 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.<ref name="Eisenhauer"/> 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.<ref name="Eisenhauer"/> It is unknown if pathophysiological interactions with docetaxel exist at this stage, however tumour type has been shown to have efficacy on cellular activity.<ref name="Lyseng-Williamson"/> Docetaxel activity is significantly greater in ovarian and breast tumours than for lung tumours.<ref name="Lyseng-Williamson"/>
==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.<ref name="FDA"/> Marketing of docetaxel as Taxotere is mainly towards the treatment of breast, prostate and other non-small cell cancers.<ref name="Taxotere.comAbout"/> Clinical data has shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, head and neck cancers, and melanoma.<ref name="Lyseng-Williamson"/><ref name="MedSafe"/>
In the treatment of breast cancer, eight phase II studies were carried out in patients with either locally advanced or metastatic breast cancer.<ref name="MedSafe"/> A total of 283 previously untreated and treated patients underwent the following dose allocations;
{| class="wikitable"
|+ Numbers of patients in each dose regiment and previous treatment state<!-- if required -->
! 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.<ref name="MedSafe"/> 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.<ref name="MedSafe"/>
Previously untreated patients in the 100 mg/m² cohort had an overall response rate of 56% and 9.4% complete responses.<ref name="MedSafe"/> 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.<ref name="MedSafe"/>
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.<ref name="MedSafe"/> 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.<ref name="MedSafe"/>
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.<ref name="MedSafe"/> 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.
{| class="wikitable"
|+ Results of an open-label, multicentre, randomised phase III study in 449 advanced breast cancer patients, comparing efficacy of docetaxel and paclitaxel <!-- if required -->
! 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
|}
Clinical studies have taken place for the treatment of non-small cell lung cancer and prostate cancer.<ref name="MedSafe"/> 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.<ref name="MedSafe"/>
The TAX 327 trial was a phase III study that showed significant survival benefit from docetaxel in androgen-independent metastatic prostate cancer.<ref name="Tannock">Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12.</ref> 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.<ref name="Tannock"/>
===Specific outcomes and benefits of treatment===
Treatment with docetaxel has the specific outcome of increasing survival time in patients with certain types of cancer.<ref name="Lyseng-Williamson"/><ref name="Clarke"/><ref name="Taxotere.comAbout"/><ref name="MedSafe"/> While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large.<ref name="MedSafe"/> Many patients survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel.<ref name="Tannock"/> Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival.<ref name="MedSafe"/><ref name="Taxotere.comSafety"/><ref name="Tannock"/> 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.<ref name="Tannock"/> 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.<ref name="MedSafe"/>
===Monitoring and combination with other drugs===
Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles.<ref name="MedSafe"/> 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.<ref name="MedSafe"/><ref name="DrugDex"/>
Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions.<ref name="MedSafe"/> 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.<ref name="MedSafe"/><ref name="Goyle">Goyle S, Maraveyas A. Chemotherapy for colorectal cancer. Dig Surg. 2005;22(6):401-14.</ref>
==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.<ref name="Lyseng-Williamson"/> Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice.<ref name="Lyseng-Williamson"/> 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.<ref name="Eisenhauer"/>
===Adverse effects===
Docetaxel is a chemotherapeutic agent and is a cytotoxic compound and so is effectively a biologically damaging drug.<ref name="Lyseng-Williamson"/><ref name="Taxotere.comPharmacokinetics"/> As with all chemotherapy, adverse effects are common and many varying side-effects have been documented.<ref name="MedSafe"/><ref name="Taxotere.comSafety"/> Because docetaxel is a cell cycle specific agent, it is cytotoxic to all dividing cells in the body.<ref name="Rangp694">Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. London: Churchill Livingstone; 2003. p. 694-8.</ref> 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.<ref name="Rangp694"/>
[[Image:Docetaxel-Adverse-Effects-Graph.jpg|thumb|320px|Incidence of commonly experienced non-haematological adverse effects reported for treatment with docetaxel. Data from 40 phase II and phase III studies (n=2045) with patients undergoing a one-hour infusion of 100 mg/m<sup>2</sup> docetaxel once every three weeks.]]
Haematological adverse effects include [[Neutropenia]] (95.5%), [[Anaemia]] (90.4%), [[Febrile]] [[neutropenia]] (11.0%) and [[Thrombocytopenia]] (8.0%).<ref name="MedSafe"/><ref name="Taxotere.comSafety"/> 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).<ref name="MedSafe"/><ref name="Taxotere.comSafety"/>
Observations of severe side effects in the above 40 phase II and phase III studies were also recorded.
[[Image:Docetaxel-Severe-Adverse-Effects-Graph.jpg|thumb|320px|Incidence of severe adverse effects reported in patients treated with docetaxel. Data from 40 phase II and phase III studies with patients undergoing a one-hour infusion of 100 mg/m<sup>2</sup> docetaxel once every three weeks.]]
Many more side effects have been reported for conjunctive and adjuvant treatment with docetaxel as well as rare post-marketing events.<ref name="MedSafe"/>
===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.<ref name="MedSafe"/><ref name="Taxotere.comSafety"/>
Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased.<ref name="MedSafe"/><ref name="DrugDex"/> Renal failure is thought not to be a significant factor for docetaxel dosage adjustment.<ref name="DrugDex"/> 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.<ref name="DrugDex"/>
Paediatric trials of docetaxel have been limited and so safety of use in patients under 16 years has not been established.<ref name="Clarke"/><ref name="DrugDex"/>
===Drug interactions===
Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved.<ref name="Clarke"/> Cisplatin, dexamethasone, doxorubicin, etoposide and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies.<ref name="Urien"/> 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%.<ref name="Clarke"/> 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.<ref name="Clarke"/>
{| class="wikitable"
|+ Common and/or likely drug-drug combinations and known side effects from drug interactions <!-- if required -->
! 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.<ref name="Clarke"/> When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.<ref name="Clarke"/>
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.<ref name="Clarke"/> 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.<ref name="Lyseng-Williamson"/> 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.<ref name="Clarke"/> Etoposide has also been shown to decrease docetaxel clearance, thought patient numbers for this observation have been low.<ref name="Clarke"/>
Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.<ref name="Tannock"/>
==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]].<ref>http://www.cnrs.fr/cw/en/pres/compress/mistpotier.html Pierre Potier, chemist, 1998 CNRS Gold Medalist</ref>
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.<ref name="USPatent">Vogel CL, Bellet RE, inventors; Aventis Pharma S.A., assignee. Use of docetaxel for treating cancers. United States patent US20016333348. 2001 Dec 25.</ref>
The Thailand Government has issued compulsory license against the patent covering Docetaxel.
Indian company Dabur will supply the generic drug to Thailand. <ref>[http://enews.mcot.net/view.php?id=3227 MCOT English News : Thailand to import generic drug from India<!-- Bot generated title -->]</ref> and
<ref>[http://www.bloomberg.com/apps/news?pid=20601091&sid=aLc_cYLhmx6U&refer=india Bloomberg.com: India & Pakistan<!-- Bot generated title -->]</ref>
==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==
{{reflist}}
==External links==
* [http://products.sanofi-aventis.us/Taxotere/taxotere.html Taxotere] (manufacturer's prescribing information)
* [http://www.taxotere.com/ Taxotere] (manufacturer's website)
* [http://www.meds-help.com/docetaxel/ Docetaxel] (patient information)
{{Chemotherapeutic agents}}
[[Category:Chemotherapeutic agents]]
[[Category:Alkaloids]]
[[cs:Docetaxel]]
[[de:Docetaxel]]
[[et:Dotsetakseel]]
[[fr:Docétaxel]]
[[ja:ドセタキセル]]
[[pt:Docetaxel]]
[[ru:Доцетаксел]]
[[fi:Doketakseli]]