Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Docetaxel: Difference between pages

{{Short description|Chemotherapy medication}}

| verifiedrevid = 461754129

| width = 250

| alt =

| image2 = Docetaxel-from-xtal-3D-sk.png

| width2 = 250

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<!--Clinical data-->

| tradename = Taxotere, Docecad, Docefrez, others

| DailyMedID = Docetaxel

| pregnancy_AU = D

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Docetaxel Use During Pregnancy | website=Drugs.com | date=4 June 2020 | url=https://www.drugs.com/pregnancy/docetaxel.html | access-date=29 October 2020}}</ref>

| routes_of_administration = [[Intravenous therapy|Intravenous]]

| ATC_prefix = L01

| ATC_suffix = CD02

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Taxotere FDA label">{{cite web | title=Taxotere- docetaxel injection, solution, concentrate | website=DailyMed | date=26 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45e6dce4-92e2-4ad1-bf11-bbcefb753636 | access-date=28 October 2020}}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Taxotere EPAR">{{cite web | title=Taxotere EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/taxotere | access-date=28 October 2020}}</ref>

| legal_status = Rx-only

| metabolism = [[Liver]]

| elimination_half-life = 11 hours

| excretion = [[Bile duct]]

| IUPHAR_ligand = 6809

| CAS_number_Ref = {{cascite|changed|CAS}}

| CAS_number = 114977-28-5

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 130581

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 699121PHCA

| KEGG_Ref = {{keggcite|changed|kegg}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| IUPAC_name = 1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-<nowiki/>{(2''R'',3''S'')-3-[(''tert''-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C43H53NO14/c1-22-26(55-37(51)32(48)30(24-15-11-9-12-16-24)44-38(52)58-39(3,4)5)20-43(53)35(56-36(50)25-17-13-10-14-18-25)33-41(8,34(49)31(47)29(22)40(43,6)7)27(46)19-28-42(33,21-54-28)57-23(2)45/h9-18,26-28,30-33,35,46-48,53H,19-21H2,1-8H3,(H,44,52)/t26-,27-,28+,30-,31+,32+,33-,35-,41+,42-,43+/m0/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = ZDZOTLJHXYCWBA-VCVYQWHSSA-N

<!-- Definition and medical uses -->

'''Docetaxel''' ('''DTX''' or '''DXL'''), sold under the brand name '''Taxotere''' among others, is a [[chemotherapy medication]] used to treat a number of types of [[cancer]].<ref name=AHFS2016/> This includes [[breast cancer]], [[head and neck cancer]], [[stomach cancer]], [[prostate cancer]] and [[non-small-cell lung cancer]].<ref name=NCI2014>{{cite web|title=FDA Approval for Docetaxel|url=https://www.cancer.gov/about-cancer/treatment/drugs/fda-docetaxel|website=National Cancer Institute|access-date=21 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221163849/https://www.cancer.gov/about-cancer/treatment/drugs/fda-docetaxel|archive-date=21 December 2016|date=2006-10-05}}</ref> It may be used by itself or along with other chemotherapy medication.<ref name=AHFS2016/> It is given by [[intravenous infusion|slow injection into a vein]].<ref name=AHFS2016>{{cite web|title=Docetaxel|url=https://www.drugs.com/monograph/docetaxel.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221162404/https://www.drugs.com/monograph/docetaxel.html|archive-date=21 December 2016}}</ref>

<!-- Side effects and mechanisms -->

Common side effects include [[hair loss]], [[cytopenia]] (low blood cell counts), numbness, shortness of breath, [[Chemotherapy-induced nausea and vomiting|nausea, vomiting]], and muscle pains.<ref name=AHFS2016/> Other severe side effects include [[allergic reactions]] and future cancers.<ref name=AHFS2016/> Docetaxel induced pneumotoxicity is also a well recognized adverse effect which has to be identified timely and treated after withholding the drug.<ref name="ReferenceA">{{cite journal | vauthors = Hettiarachchi SM, Thilakaratne D, Dharmasena D, Rathnapala A, Abeysinghe P, Perera E | title = Docetaxel-induced interstitial lung disease among patients with breast cancer: a case series and review of literature | journal = Respirology Case Reports | volume = 9 | issue = 7 | pages = e00802 | date = July 2021 | pmid = 34136263 | pmc = 8200505 | doi = 10.1002/rcr2.802 }}</ref> Side effects are more common in people with [[liver problems]].<ref name=AHFS2016/> Use during [[pregnancy]] may harm the baby.<ref name=AHFS2016/> Docetaxel is in the [[taxane]] family of medications.<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=622|edition=69}}</ref> It works by disrupting the normal function of [[microtubules]] and thereby stopping [[cell division]].<ref name=AHFS2016/>

<!-- History and culture -->

Docetaxel was patented in 1986 and approved for medical use in 1995.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=512|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA512|language=en|url-status=live|archive-url=https://web.archive.org/web/20161221092059/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA512|archive-date=2016-12-21}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> Docetaxel is available as a [[generic medication]].<ref name=AHFS2016/>

==Medical uses==

[[File:Chemotherapy with acral cooling.jpg|thumb|A woman being treated with docetaxel chemotherapy for [[breast cancer]]. Cold mittens and [[Wine accessory#Wine coolers|wine cooler]]s are placed on her hands and feet to prevent deleterious effects on the nails. Similar strategies can be used to prevent hair loss.]]

Docetaxel is used in the treatment of various cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancer.<ref name=AHFS2016 /> Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, and head and neck cancers and melanoma.<ref name="Lyseng-Williamson"/> In hormone-refractory prostate cancer docetaxel improves life expectancy and overall life quality.<ref>{{cite journal | vauthors = Shelley M, Harrison C, Coles B, Staffurth J, Wilt TJ, Mason MD | title = Chemotherapy for hormone-refractory prostate cancer | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD005247 | date = October 2006 | pmid = 17054249 | doi = 10.1002/14651858.CD005247.pub2 }}</ref>

The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule. While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.<ref name="accessdata.fda.gov">{{cite web | url = http://accessdata.fda.gov | archive-url=https://web.archive.org/web/20140428162939/http://www.accessdata.fda.gov/ | archive-date=2014-04-28 | title = Docetaxel Package Insert | date = February 2011 | publisher = U.S. Food and Drug Administration }}</ref>

===Outcomes===

Treatment with docetaxel increases survival time in people with certain types of cancer.<ref name="Taxotere.comAbout"/><ref name="Lyseng-Williamson"/><ref name="Clarke"/> 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 people survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel.<ref name="Tannock">{{cite journal |vauthors=Tannock IF, de Wit R, Berry WR, et al |title=Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer |journal=N. Engl. J. Med. |volume=351 |issue=15 |pages=1502–12 |date=October 2004 |pmid=15470213 |doi=10.1056/NEJMoa040720 |doi-access=free }}</ref> 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="Tannock"/><ref name="Taxotere.comSafety"/> 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"/>

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"/>

===Breast cancer===

Docetaxel and paclitaxel have comparable efficacy metastatic breast cancer but paclitaxel has less severe side effects.<ref name="informahealthcare.com">{{cite journal | vauthors = Qi WX, Shen Z, Lin F, Sun YJ, Min DL, Tang LN, He AN, Yao Y | display-authors = 6 | title = Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials | journal = Current Medical Research and Opinion | volume = 29 | issue = 2 | pages = 117–25 | date = February 2013 | pmid = 23216340 | doi = 10.1185/03007995.2012.756393 | s2cid = 20632486 }}</ref> Additionally, it has been noted that docetaxel is prone to cellular drug resistance via a variety of different mechanisms.<ref>{{cite journal | vauthors = Alken S, Kelly CM | title = Benefit risk assessment and update on the use of docetaxel in the management of breast cancer | journal = Cancer Management and Research | volume = 5 | pages = 357–65 | date = October 2013 | pmid = 24143122 | pmc = 3798099 | doi = 10.2147/CMAR.S49321 | doi-access = free }}</ref>

===Monitoring and combination use===

Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles.<ref name="MedSafe"/> Treatment is given under the supervision of an oncologist. Strict monitoring of blood cell counts, liver function, serum electrolytes, serum creatinine, heart function, oxygen saturation and fluid retention is required detect adverse reactions and toxicity so that treatment can be modified or terminated if necessary.<ref name="DrugDex"/>

Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions.<ref name="MedSafe"/> 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="Goyle">{{cite journal |vauthors=Goyle S, Maraveyas A |title=Chemotherapy for colorectal cancer |journal=Dig Surg |volume=22 |issue=6 |pages=401–14 |year=2005 |pmid=16479107 |doi=10.1159/000091441 |s2cid=27601641 |url=http://content.karger.com/produktedb/produkte.asp?DOI=91441&typ=pdf |url-status=live |archive-url=https://web.archive.org/web/20121006101922/http://content.karger.com/produktedb/produkte.asp?DOI=91441&typ=pdf |archive-date=2012-10-06 }}</ref>

==Side effects==

[[File: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/m² docetaxel once every three weeks.]]

[[File: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/m² docetaxel once every three weeks.]]

Docetaxel is a cytotoxic chemotherapeutic agent.<ref name="Lyseng-Williamson"/><ref name="Taxotere.comPharmacokinetics"/> As with all chemotherapy, adverse effects are common, and many 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|hair loss]] occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the 'common and frequent' classification.<ref name="Rangp694"/>

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"/>

Taxane-induced pneumotoxicity is rare. However, 1–5% of patients taking docetaxel may develop severe pneumotoxicity. Patients may develop exertional breathlessness and desaturation which needs to be detected early. Chest X-Ray may show bilateral opacities and High Resolution CT chest may reveal Organizing Pneumonia (OP) pattern or Non-Specific Organizing Pneumonia (NSIP) pattern or a combination. Docetaxel-induced DPLD is a fatal adverse effect, which can be managed by the cessation of the drug and starting on steroids in adequate doses.<ref name="ReferenceA"/>

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.<ref name="MedSafe"/>

===Contraindications and patient factors===

Docetaxel is contraindicated for use with patients with a baseline neutrophil count less than 1500 cells/µL, 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"/> [[Kidney 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 people who develop grade 3 or 4 diarrhea 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"/>

===Pregnancy===

Based on the limited data available, docetaxel appears to be safe in pregnancy if administered during the second and third trimesters; however, maternal and fetal risks should be weighed against benefits to determine the appropriate course of action.<ref name="pmid23470115">{{cite journal | vauthors = Koren G, Carey N, Gagnon R, Maxwell C, Nulman I, Senikas V |title=Cancer chemotherapy and pregnancy |journal=J Obstet Gynaecol Can |volume=35 |issue=3 |pages=263–80 |date= March 2013 |pmid=23470115 |doi= 10.1016/s1701-2163(15)30999-3|doi-access=free }}</ref><ref name="pmid22875836">{{cite journal | vauthors = Cardonick E, Bhat A, Gilmandyar D, Somer R |title=Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature |journal=Ann. Oncol. |volume=23 |issue=12 |pages=3016–23 |year=2012 |pmid=22875836 |doi=10.1093/annonc/mds170 |doi-access=free }}</ref>

As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred.<ref name="ReferenceB">Gideon Koren, Nathalie Carey, Robert Gagnon, et al. Cancer Chemotherapy and Pregnancy, "Journal of Obstetrics and Gynecology Canada", March 2013</ref> Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent.<ref name="ReferenceB"/> Further studies are needed to better assess the safety of docetaxel in pregnancy and determine appropriate dosing in pregnant women.

===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 the following: 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, though 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"/>

==Chemistry==

Docetaxel is of the chemotherapy drug class; [[taxane]], and is a semi-synthetic analogue of [[paclitaxel]] (Taxol), an extract from the bark of the rare Pacific yew tree, ''[[Taxus brevifolia]]''.<ref name="Clarke">{{cite journal |vauthors=Clarke SJ, Rivory LP |title=Clinical pharmacokinetics of docetaxel |journal=Clin Pharmacokinet |volume=36 |issue=2 |pages=99–114 |date=February 1999 |pmid=10092957 |doi=10.2165/00003088-199936020-00002|s2cid=29088907 }}</ref> 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 more readily available leaves of the [[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 carbamate ester exists on the phenylpropionate side chain instead of the benzamide in paclitaxel. 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&nbsp;mg and 80&nbsp;mg Taxotere single-dose vials of concentrated anhydrous docetaxel in [[polysorbate 80]].<ref name="Clarke"/><ref name="MedSafe">{{cite web | title = Taxotere Docetaxel concentrate for infusion | work = Medsafe | url = http://www.medsafe.govt.nz/profs/datasheet/d/DocetaxelEbeweinj.htm | access-date = 10 June 2010 |url-status=dead|archive-url=https://web.archive.org/web/20100603164834/http://www.medsafe.govt.nz/profs/Datasheet/d/DocetaxelEbeweinj.htm |archive-date=2010-06-03 | orig-date = 6 February 2006 }}</ref> The solution is a clear brown-yellow containing 40&nbsp;mg docetaxel and 1040&nbsp;mg polysorbate 80 per mL.<ref name="MedSafe"/> 20&nbsp;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&nbsp;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&nbsp;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&nbsp;mg vials may be stored for 24 months below 25&nbsp;°C away from light and 80&nbsp;mg vials for 26 months in the same conditions.<ref name="MedSafe"/>

Recently Sanofi has got approval for one-vial formulation.{{Citation needed|date=June 2010}} 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 [[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">{{cite journal |vauthors=Snyder JP, Nettles JH, Cornett B, Downing KH, Nogales E |title=The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=9 |pages=5312–6 |date=April 2001 |pmid=11309480 |pmc=33206 |doi=10.1073/pnas.051309398 |bibcode=2001PNAS...98.5312S |doi-access=free }}</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 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.<ref name="Snyder"/>

==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%.<ref name="DrugDex">{{cite web | title = Drugdex Evaluations: Docetaxel | work = Thomson MICROMEDEX | url = http://www.library.auckland.ac.nz/databases/learn_database/public.asp?record=micromedex#Drugdex | date = 26 September 2006 }}</ref> In practice, docetaxel is administered intravenously only to increase dose precision.<ref name="Clarke"/><ref name="MedSafe"/><ref name="Taxotere.comSafety">{{cite web | title = Taxotere for Healthcare Professionals: Efficacy and Safety | publisher = Sanofi-Aventis U.S. LLC | url = http://www.taxotere.com/professional/about/efficacy_safety.do |access-date= 2 October 2006 |url-status=live |archive-url=https://web.archive.org/web/20061111064251/http://www.taxotere.com/professional/about/efficacy_safety.do |archive-date= 11 November 2006}}</ref><ref name="Pharmac">{{cite report | title = New Zealand Pharmaceutical Schedule. Wellington | work = PHARMAC | date = 2006 | page = 133 }}</ref> Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100&nbsp;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&nbsp;°C and pH 7.4<ref name="Urien">{{cite journal |vauthors=Urien S, Barré J, Morin C, Paccaly A, Montay G, Tillement JP |title=Docetaxel serum protein binding with high affinity to alpha 1-acid glycoprotein |journal=Invest New Drugs |volume=14 |issue=2 |pages=147–51 |year=1996 |pmid=8913835 |doi=10.1007/BF00210785 |s2cid=24497910 }}</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"/> Docetaxel interacted little with [[erythrocyte]]s and was unaffected by the polysorbate 80 in its storage medium.<ref name="Clarke"/><ref name="Urien"/> Polysorbate 80 may be the cause of hypersensitivity reasons in taxanes as recent studies indicated.<ref name="pmid29796927">{{cite journal | vauthors = Schwartzberg LS, Navari RM | title = Safety of Polysorbate 80 in the Oncology Setting | journal = Advances in Therapy | volume = 35 | issue = 6 | pages = 754–767 | date = June 2018 | pmid = 29796927 | pmc = 6015121 | doi = 10.1007/s12325-018-0707-z }}</ref><ref>{{cite web |url=http://www.ehealthme.com/ds/taxotere/hypersensitivity |title=Taxotere and Hypersensitivity, a phase IV clinical study of FDA data - eHealthMe |access-date=2012-05-09 |url-status=live |archive-url=https://web.archive.org/web/20150701165304/http://www.ehealthme.com/ds/taxotere/hypersensitivity |archive-date=2015-07-01 }}</ref>

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&nbsp;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&nbsp;mg.h/L.<ref name="Clarke"/> The Cmax of docetaxel was found to be 4.15 ± 1.35&nbsp;mg/L.<ref name="Baker">{{cite journal |vauthors=Baker SD, Zhao M, Lee CK, etal |title=Comparative pharmacokinetics of weekly and every-three-weeks docetaxel |journal=Clin. Cancer Res. |volume=10 |issue=6 |pages=1976–83 |date=March 2004 |pmid=15041715 |url=http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15041715 |doi=10.1158/1078-0432.CCR-0842-03|doi-access=free }}</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">{{cite web | title = Taxotere.com for Healthcare Professionals: Pharmacokinetics | publisher = Sanofi-aventis U.S. LLC. | url = http://www.taxotere.com/professional/about/pharmacokinetics.do | access-date = 2 October 2006 |url-status=live |archive-url=https://web.archive.org/web/20061111064303/http://www.taxotere.com/professional/about/pharmacokinetics.do |archive-date=2006-11-11 | date = 23 September 2006 }} </ref><ref name="Guitton">{{cite journal |vauthors=Guitton J, Cohen S, Tranchand B, etal |title=Quantification of docetaxel and its main metabolites in human plasma by liquid chromatography/tandem mass spectrometry |journal=Rapid Commun. Mass Spectrom. |volume=19 |issue=17 |pages=2419–26 |year=2005 |pmid=16059877 |doi=10.1002/rcm.2072 |bibcode=2005RCMS...19.2419G }}</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 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.<ref name="Urien"/> The following model represents docetaxel clearance in humans:

<div style='text-align: center;'>'''CL = BSA · (22.1 − 3.55·AAG − 0.095·AGE + 0.2245·ALB) · (1 − 0.334·HEP12)'''</div>

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).<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&nbsp;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">{{cite journal |vauthors=Yvon AM, Wadsworth P, Jordan MA |title=Taxol Suppresses Dynamics of Individual Microtubules in Living Human Tumor Cells |journal=Mol. Biol. Cell |volume=10 |issue=4 |pages=947–59 |date=April 1999 |pmid=10198049 |pmc=25218 |doi=10.1091/mbc.10.4.947}}</ref> This binding stabilizes 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">{{cite journal |vauthors=Lyseng-Williamson KA, Fenton C |title=Docetaxel: a review of its use in metastatic breast cancer |journal=Drugs |volume=65 |issue=17 |pages=2513–31 |year=2005 |pmid=16296875 |doi=10.2165/00003495-200565170-00007}}</ref><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 [[Guanosine triphosphate|GTP]].<ref name="Lyseng-Williamson"/><ref name="Eisenhauer">{{cite journal |vauthors=Eisenhauer EA, Vermorken JB |title=The taxoids. Comparative clinical pharmacology and therapeutic potential |journal=Drugs |volume=55 |issue=1 |pages=5–30 |date=January 1998 |pmid=9463787 |doi=10.2165/00003495-199855010-00002|s2cid=46967845 }}</ref><ref name="RxListCP">{{cite web | title = Docetaxel: Clinical Pharmacology. | work = RxList | url= http://www.rxlist.com/cgi/generic3/docetaxel_cp.htm |access-date=2006-10-02 |url-status=dead|archive-url=https://web.archive.org/web/20061022202456/http://www.rxlist.com/cgi/generic3/docetaxel_cp.htm |archive-date=2006-10-22 | orig-date = 24 September 2006 }}</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"/> This can lead to [[mitotic catastrophe]].<ref>{{cite journal | vauthors = Denisenko TV, Sorokina IV, Gogvadze V, Zhivotovsky B | title = Mitotic catastrophe and cancer drug resistance: A link that must to be broken | journal = Drug Resistance Updates | volume = 24 | pages = 1–12 | date = January 2016 | pmid = 26830311 | doi = 10.1016/j.drup.2015.11.002 }}</ref> 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 of replication caused by docetaxel leads to apoptosis of tumour cells and is the basis of docetaxel use as a cancer treatment.<ref name="Eisenhauer"/> Docetaxel activity is significantly greater in ovarian and breast tumours than for lung tumours.<ref name="Lyseng-Williamson"/>

==Society and culture==

===Discovery, regulation and marketing===

Docetaxel is marketed worldwide under the name Taxotere by [[Sanofi-Aventis]]<ref name="Taxotere.comAbout">{{cite web | title = Taxotere for Healthcare Professionals: About. | publisher = Sanofi-Aventis U.S. LLC. | url = http://www.taxotere.com/professional/about/index.do |access-date=2006-10-02 |url-status=live |archive-url=https://web.archive.org/web/20061109200959/http://www.taxotere.com/professional/about/index.do |archive-date=2006-11-09 | date = 16 September 2006 }}</ref> as well as Docefrez by Sun Pharma Global and Zytax by Zydus.<ref>{{cite web |url=http://www.rxlist.com/docefrez-drug.htm |title=Docefrez (Docetaxel): Uses, Dosage, Side Effects, Interactions, Warning |access-date=2014-04-20 |url-status=live |archive-url=https://web.archive.org/web/20140512154932/http://www.rxlist.com/docefrez-drug.htm |archive-date=2014-05-12 }}</ref> Annual sales of Taxotere in 2010 were €2.122 billion ({{US$}}3.1 billion). The patent expired in 2010.{{Citation needed|date=May 2011}}

Docetaxel 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 [[paclitaxel]] (Taxol) using the local [[European yew]].<ref>{{cite web |url=http://www.cnrs.fr/cw/en/pres/compress/mistpotier.html |title=Pierre Potier, chemist, 1998 CNRS Gold Medalist |access-date=2007-07-12 |url-status=dead|archive-url= https://web.archive.org/web/20070623011443/http://www.cnrs.fr/cw/en/pres/compress/mistpotier.html |archive-date=2007-06-23 | work = French National Centre for Scientific Research (CNRS) }}</ref>

===Costs===

In the UK (in 2009) The cost of six cycles (18 weeks) of docetaxel at a dose of 75&nbsp;mg/m2 IV every 21 days is £5,262 (based on an average [[body surface area]] 1.75 m²).<ref>{{cite web | url = http://www.haps.bham.ac.uk/publichealth/horizon/outputs/documents/2009/jan-apr/Cabazitaxel.pdf | archive-url = https://web.archive.org/web/20091117173920/http://www.haps.bham.ac.uk/publichealth/horizon/outputs/documents/2009/jan-apr/Cabazitaxel.pdf | archive-date = 17 November 2009 | title = Cabazitaxel (XRP-6258) for hormone refractory, metastatic prostate cancer – second line after docetaxel | date = April 2009 | work = The National Horizon Scanning Centre Research Programme | publisher = National Institute for Health Research, U.K. National Health Service }}</ref><ref>{{cite web | title = TA101 Prostate cancer (hormone-refractory) - docetaxel: analysis of cost impact | location = London | publisher = NICE | date = September 2006 | url = http://www.nice.org.uk/guidance/index.jsp?action=download&o=33354 |access-date=2010-06-10 |url-status=live |archive-url=https://web.archive.org/web/20090321095030/http://www.nice.org.uk/guidance/index.jsp?action=download&o=33354 |archive-date=2009-03-21 }}</ref>

==References==

{{Reflist}}

{{Chemotherapeutic agents}}

{{Xenobiotic-sensing receptor modulators}}

{{Portal bar|Medicine}}

[[Category:Acetate esters]]

[[Category:Benzoate esters]]

[[Category:Carbamates]]

[[Category:Microtubule inhibitors]]

[[Category:Mitotic inhibitors]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Taxanes]]

[[Category:Tert-Butyl esters]]

[[Category:World Health Organization essential medicines]]

[[Category:Sanofi]]