'''Paclitaxel''' is a [[mitotic inhibitor]] used in [[cancer]] [[chemotherapy]]. It was discovered in a [[National Cancer Institute]] program at the [[Research Triangle Institute]] in 1967 when [[Monroe E. Wall]] and [[Mansukh C. Wani]] isolated it from the bark of the Pacific yew tree, ''[[Taxus brevifolia]]'' and named it 'taxol'. When it was developed commercially by [[Bristol-Myers Squibb]] (BMS) the generic name was changed to 'paclitaxel' and the BMS compound is sold under the trademark 'Taxol'. In this formulation paclitaxel is dissolved in Cremophor EL, a polyoxyethylated castor oil, as a delivery agent since paclitaxel is not soluble in water. A newer formulation, in which paclitaxel is bound to [[Human serum albumin|albumin]] as the delivery agent ([[Protein-bound paclitaxel]]), is sold commercially by [http://www.abraxisbio.com Abraxis BioScience] under the trademark [http://www.paclitaxel.com paclitaxel].<ref name="paclitaxel">"[http://www.fda.gov/cder/foi/label/2005/021660lbl.pdf paclitaxel Drug Information]." ''[[Food and Drug Administration]].'' [[January 7]], [[2005]]. Retrieved on [[March 9]], [[2007]].</ref>
Paclitaxel is now used to treat patients with [[lung cancer|lung]], [[ovarian cancer|ovarian]], [[breast cancer]], head and neck cancer, and advanced forms of [[Kaposi's sarcoma]]. Paclitaxel is also used for the prevention of [[restenosis]].
Paclitaxel works by interfering with normal [[microtubule]] breakdown during cell division. Together with [[docetaxel]], it forms the drug category of the [[taxane]]s. It was the subject of a notable [[Paclitaxel total synthesis|total synthesis]] by [[Robert A. Holton]].
As well as offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug. There was originally concern because of the environmental impact of its original sourcing, no longer used, from the Pacific yew. The assignment of rights, and even the name itself, to BMS were the subject of public debate and Congressional hearings.
==History==
===The plant screening program, isolation, and preclinical trials===
[[Image:Paclitaxel JMolBiol 2001 1045.jpg|left|thumbnail|200px|Crystal structure of paclitaxel<ref>{{cite journal |authors=Löwe, J.; Downing, K. H.; Nogales, E. |title=Refined structure of αβ-tubulin at 3.5 Å resolution |journal=Journal of Molecular Biology |volume=313 |issue=5 |year=2001 |pages=1045–1057 |doi=10.1006/jmbi.2001.5077 }}</ref>]]
In 1955 the [[National Cancer Institute]] (NCI) set up the [[Cancer Chemotherapy National Service Center]] (CCNSC) to act as a public screening centre for anti-cancer activity in compounds submitted by external institutions and companies<ref>{{cite book
| last = Goodman
| first = Jordan
| coauthors = Walsh, Vivien
| title = The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug
| publisher = Cambridge University Press
| date = 2001
| isbn = 0 521 56123 X}}, p17</ref> Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who was employed there from 1958 onwards, had had experience of natural product derived compounds and began a plant screening operation.<ref>Goodman and Walsh, p22</ref> After some years of informal arrangements, in July 1960 the NCI commissioned [[Department of Agriculture|USDA]] botanists to collect samples from about 1000 plant species per year.<ref>Goodman and Walsh p25, p28</ref> On August 21st, 1962, one of those botanists, [[Arthur S. Barclay]], collected bark from a single Pacific yew tree, ''[[Taxus brevifolia]]'', in a forest north of the town of [[Packwood, Washington]] as part of a four month trip collecting material from over 200 different species.<ref>Goodman and Walsh, p51</ref> The material was then processed by a number of specialist CCNSC subcontractors and one of the ''Taxus'' samples was found to be cytotoxic in a cellular assay on 22 May 1964.<ref>Goodman and Walsh, p51</ref>
Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by [[Monroe E. Wall]] in [[Research Triangle Park]], [[North Carolina]], began work on fresh ''Taxus'' samples, isolating the active ingredient in September 1966 and announcing their findings at an April 1967 [[American Chemical Society]] meeting in Miami Beach.<ref>{{cite journal |author=Wall ME, Wani MC |title=Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture |journal=Cancer Res. |volume=55 |issue=4 |pages=753-60 |year=1995 |pmid=7850785 |doi=}}</ref>. They named the pure compound 'taxol' in June 1967. <ref>Goodman and Walsh p51</ref>
Wall and his colleague Wani published their results, including the chemical structure, in 1971.<ref>{{cite journal | author = Wani M, Taylor H, Wall M, Coggon P, McPhail A | title = Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from ''Taxus brevifolia'' | journal = J Am Chem Soc | volume = 93 | issue = 9 | pages = 2325-2327 | year = 1971 | id = PMID 5553076}}</ref>.
The NCI continued to commission work to collect more ''Taxus'' bark and to isolate increasing quantities of taxol. By 1969 28kg of crude extract had been isolated from almost 1,200kg of bark, although this ultimately yielded only 10g of pure material. <ref> Goodman and Walsh p81</ref> But for several years no use was made of the compound by the NCI. In 1975 it was shown to be active in another ''in vitro'' system ; two years later a new department head reviewed the data and finally recommended that taxol be moved on to the next stage in the discovery process. <ref> Goodman and Walsh p79, p81</ref> This required increasing quantities of purified taxol, up to 600g, and in 1977 a further request for 7,000 pounds of bark was made.
In 1978, two NCI researchers published a report showing that taxol was mildly effective in leukaemic mice. <ref>
{{cite journal | author = Fuchs, David A and Johnson, Randall K | title = Cytologic evidence that taxol, an antineoplastic agent from ''Taxus brevifolia'', acts as a mitotic spindle poison | journal = Cancer Treatment Reports | volume = 62 | pages = 1219-1222 | year = 1978 | id = PMID 688258 }}</ref>
In November 1978, taxol was shown to be effective in [[xenograft]] studies.<ref> Goodman and Walsh 95</ref>
Meanwhile taxol began to be well known in the cell biology, as well as the cancer community, with a publication in early 1979 by [[Susan B. Horwitz]], a molecular pharmacologist at [[Albert Einstein College of Medicine]], that showed that taxol had a previously unknown mechanism of action involving the stabilisation of [[microtubules]]. Together with formulation problems, this increased interest from researchers meant that by 1980 the NCI envisaged needing to collect 20,000 pounds of bark. <ref> Goodman and Walsh p97</ref>.
Animal toxicology studies were complete by June 1982, and in November NCI applied for the [[INDA]] necessary to begin clinical trials in humans.<ref> Goodman and Walsh p97</ref>.
===Early clinical trials, supply and the transfer to BMS===
[[Phase I]] clinical trials began in April 1984 and the decision to start [[Phase II]] trials was made a year later.<ref> Goodman and Walsh 115</ref> These larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase II trials to begin by the end of 1986. But by then it was recognised that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. This unprecedentedly large amount brought ecological concerns about the impact on yew populations into focus for the first time as local politicians and foresters expressed unease at the program<ref> Goodman and Walsh 120</ref>.
The first public report from a phase II trial in May 1988 showed an effect in melanoma patients and a remarkable response rate of 30% in patients with refractory ovarian cancer.<ref>
{{cite journal | author = Rowinsky, EK and others | title = Phase II study of taxol in advanced epithelial malignancies | journal = Proceedings of the Association of Clinical Oncology | volume = 7 | pages = 136 | year = 1988 }}</ref>.
At this point Gordon Cragg of the NCI's Natural Product Branch calculated that the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in the US would require the destruction of 360,000 trees annually. For the first time, serious consideration was given to the problem of supply.<ref> Goodman and Walsh 120</ref>.
Because of the practical and in particular the financial scale of the programme needed, the NCI decided to seek association with a pharmaceutical company, and in August 1989 it published a [[Cooperative Research and Development Agreement]] (CRADA) offering its current stock and supply from current bark stocks, together with proprietary access to the data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. In the words of Goodman and Welsh, authors of a substantial scholarly book on taxol, <blockquote>
[The NCI] was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)
<ref>Goodman and Walsh p120</ref>
</blockquote>
Although widely advertised, only four companies responded to the CRADA, including [[Bristol-Myers Squibb]] (BMS),
who were selected as the partner in December 1989. The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992. While it seems clear that the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the [[General Accounting Office]] in 2003 which concluded that the NIH had failed to ensure value for money.<ref>{{cite web|url=http://wyden.senate.gov/leg_issues/reports/taxol.pdf|title=Technology Transfer: NIH-Private Sector Partnership in the Development of Taxol}}</ref> In related CRADAs with the [[USDA]] and [[Department of the Interior]], Bristol-Myers Squibb were given exclusive first refusal on all Federal supplies of ''Taxus brevifolia''.
This exclusive contract lead to some criticism for giving BMS a "cancer [[monopoly]]."<ref name="monopoly">Nader, Ralph; Love, James. "[http://findarticles.com/p/articles/mi_m1295/is_n2_v57/ai_13417481 Looting the medicine chest: how Bristol-Myers Squibb made off with the public's cancer research]." ''[[The Progressive]].'' February, 1993. Retrieved on [[March 9]], [[2007]].</ref>
Eighteen months after the CRADA, BMS filed a [[new drug application]] (NDA) which was given FDA approval at the very end of 1992.
<ref>Goodman and Walsh p120</ref>
Although there was no patent on the compound, the provisions of the [[Waxman-Hatch Act]] gave Bristol-Myers Squibb five years exclusive marketing rights.
In 1990, Bristol-Myers Squibb applied to trademark the name 'taxol' as Taxol®. This was controversially approved in 1992. At the same time, 'paclitaxel' replaced 'taxol' as the generic name of the compound. Critics, including the journal ''[[Nature]]'', argued that the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested that the trademark should not have been awarded and the BMS should renounce its rights to it.<ref>{{cite journal |author= |title=Names for hi-jacking |journal=Nature |volume=373 |issue=6513 |pages=370 |year=1995 |pmid=7830775 |doi=10.1038/373370a0}}</ref> BMS argued that changing the name would cause confusion among oncologists and possibly endanger the health of patients. BMS has continued to defend its rights to the name in the courts.<ref>Goodman and Walsh p170</ref>
BMS have also been criticised for misrepresentation by Goodman and Walsh, who quote from a company report saying that
<blockquote>
It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17'<ref>Bristol-Myers Squibb, The development of Taxol®(paclitaxel), March 1997, as cited in Goodman and Walsh p2</ref>
</blockquote>
This quote is strictly speaking accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing the isolation who named the compound taxol and it was not referred to in any other way for more than twenty years.
Annual sales peaked in 2000, reaching [[US$]]1.6 billion; paclitaxel is now available in generic form.
==Production==
[[Image:PacificYew 8566.jpg|thumb|right|Undisturbed Pacific Yew bark contains paclitaxel and related chemicals.]]
[[Image:Yew bark Taxol PD.jpg|thumbnail|right|The bark is peeled and processed to provide paclitaxel.]]
From 1967 to 1993, almost all paclitaxel produced was derived from bark from the Pacific yew, the harvesting of which kills the tree in the process. The processes used were descendants of the original isolation method of Wall and Wani; by 1987 the NCI had
contracted [[Hauser Chemical Research]] of Boulder, Colorado to handle bark on the scale needed for Phase II and III trials. While there was considerable uncertainty about how large the wild population of ''Taxus brevifola'' was and what the eventual demand for taxol would be, it had been clear for many years that an alternative, sustainable source of supply would be needed. Initial attempts used needles from the tree, or material from other related ''Taxus'' species, including cultivated ones. But these attempts were bedevilled by the relatively low and often highly variable yields obtained. It was not until the early 1990s, at a time of increased sensitivity to the ecology of the forests of the Pacific North West, that taxol was successfully extracted on a clinically useful scale from these sources. <ref>Goodman and Walsh pp172-175</ref>
From the late 1970s, chemists in the US and France had been interested in taxol. A number of US groups, including one
led by [[Robert A. Holton]], attempted a [[total synthesis]] of the molecule, starting from [[petrochemical]]-derived starting materials. This work was primarily motivated as a way of generating chemical knowledge, rather than with any expectation of developing a practical production technique. By contrast the French group of [[Pierre Potier]] at the [[CNRS]] quickly recognised the problem of yield. His laboratory was on a campus populated by the related yew ''Taxus baccata'', so that needles were available locally in large quantity. By 1981 he had shown that it was feasible to isolate relatively large quantities of the compound [[10-deacetylbaccatin]], a plausible first step for a semi-synthetic production route to taxol. By 1988 he copublished such a semisynthetic route from needles of ''Taxus baccata''.<ref>Goodman and Walsh pp100-101</ref>
The view of the NCI, however, was that even this route was not practical.<ref name="Stephenson_2003">{{cite journal|title=A tale of taxol|author=Stephenson, Frank|journal=Florida State University Research In Review|volume=12|number=3|date=Fall|year=2003|url=http://www.rinr.fsu.edu/fall2002/taxol.html}}</ref>
By 1988, and particularly with Potier's publication, it was clear to Holton as well that a practical semi-synthetic production route would be important. By late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process. [[Florida State University]], where Holton worked, signed a deal with [[Bristol-Myers Squibb]] to license this and future patents. In 1992, Holton patented an improved process with an 80% yield. BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew. <ref name="Stephenson_2003"/> In early 1993, BMS were able to announce that they would cease reliance on Pacific yew bark by the end of 1995, effectively terminating the ecological controversy over its use. This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their CRADA application of 1989.
Currently, all paclitaxel production for BMS uses plant cell fermentation (PCF) technology developed by the biotechnology company [[Phyton (biotechnology company)|Phyton]] and carried out at their plant in Germany.<ref>{{cite web|title=Phyton news release|url=http://www.phytonbiotech.com/news_031215.htm}}</ref> This starts from a specific taxus cell line propagated in aqueous medium in large fermentation tanks. Paclitaxel is then extracted directly, purified by chromatography and isolated by crystallization. Compared to the semisynthesis, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.<ref name="2004_EPA_award">{{cite web|url=http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa04.html|title= 2004 Greener Synthetic Pathways Award: Bristol-Myers Squibb Company: Development of a Green Synthesis for Taxol® Manufacture via Plant Cell Fermentation and Extraction}}</ref>
In 1993 it was discovered that taxol was coincidentally produced in a newly described [[fungus]] living in the yew tree, see: Stierle, A., [[Gary Strobel]], et al. (1993). "Taxol and Taxane Production by Taxomyces-Andreanae, an Endophytic Fungus of Pacific Yew." Science 260(5105): 214-216. It has since been found in a number of other [[Endophyte|endophytic]] fungi, including ''[[Nodulisporium sylviforme]]''<ref name="ZhaoK">Zhao, K.; et al. "[http://www.sciencepub.org/nature/0202/09zhao.pdf Study on the Preparation and Regeneration of Protoplast from Taxol-producing Fungus ''Nodulisporium sylviforme']." ''Nature and Science.'' [[2004]]. '''2''' (2). pp. 52-59.</ref>, opening the possibility of taxol production by culturing one of these fungal species.
The initial motivation for synthetic approaches to paclitaxel included the opportunity to create closely related compounds. Indeed this approach led to the development of [[docetaxel]].
==Mechanism of action==
Paclitaxel interferes with the normal function of [[microtubule]] breakdown. Whereas drugs like [[colchicine]] cause the depolymerization of microtubules, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its [[cytoskeleton]] in a flexible manner. Specifically, paclitaxel binds to the [[tubulin|β subunit of tubulin]]. Tubulin is the "building block" of microtubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a mechanism to transport other cellular components. For example, during [[mitosis]], microtubules position the [[chromosome]]s during their replication and subsequent separation into the two daughter-cell nuclei.<ref name="KumarN">Kumar, N. "[http://www.jbc.org/cgi/reprint/256/20/10435 Taxol-induced Polymerization of Purified Tubulin]." ''[[Journal of Biological Chemistry]].'' 1981. Vol. 256, No. 20, 10435-10441.</ref>
Further research has indicated that paclitaxel induces programmed cell death ([[apoptosis]]) in cancer cells by binding to an apoptosis stopping protein called [[Bcl-2 protein|Bcl-2]] (B-cell leukemia 2) and thus arresting its function.
In addition to stabilizing microtubules paclitaxel may act as a molecular mop by sequestering free tubulin effectively depleting the cells supply of tubulin monomers and/or dimers. This activity may trigger the aforementioned apoptosis.<ref>Foss M, Wilcox BWL, Alsop GB, Zhang D (2008) Taxol Crystals Can Masquerade as Stabilized Microtubules. PLoS ONE 3(1): e1476 doi:10.1371/journal.pone.0001476</ref>
One common characteristic of most [[cancer cell]]s is their rapid rate of cell division. In order to accommodate this, the cytoskeleton of a cell undergoes extensive restructuring. Paclitaxel is an effective treatment for aggressive cancers because it adversely affects the process of cell division by preventing this restructuring. Cancer cells are also destroyed by the aforementioned anti-Bcl-2 mechanism. Other cells are also affected adversely, but since cancer cells divide much faster than non-cancerous cells, they are far more susceptible to paclitaxel treatment.
==Clinical use==
Taxol is approved in the UK for ovarian cancer, breast cancer, lung cancer. It is also used in the treatment of [[Kaposi's sarcoma]].<ref name=Saville>{{cite journal | author = Saville M, Lietzau J, Pluda J, Feuerstein I, Odom J, Wilson W, Humphrey R, Feigal E, Steinberg S, Broder S | title = Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. | journal = Lancet | volume = 346 | issue = 8966 | pages = 26-8 | year = 1995 | month=July 1 | pmid=7603142}}</ref>
It is recommended in [[NICE]] guidance of June 2001 that it should be used for non-small cell lung cancer in patients unsuitable for curative treatment, and in first-line and second-line treatment of ovarian cancer. In September 2001 NICE recommended that paclitaxel should be available for the treatment of advanced breast cancer after the failure of anthracyclic chemotherapy, but that its first-line use should be limited to clinical trials. In September 2006 NICE recommended that paclitaxel should ''not'' be used in the adjuvant treatment of early node-positive breast cancer.<ref>{{cite web|url=http://www.bnf.org/bnf/bnf/current/21850.htm|title=British National Formulary}}</ref>
The cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, is about £4000.<ref>{{cite web|title=NICE Guidance TA108|url=http://guidance.nice.org.uk/TA108/guidance/pdf/English}}</ref>
===Similar compounds===
In [[January 2005]], the [[Food and Drug Administration]] (FDA) approved [http://www.paclitaxel.com paclitaxel®]([[protein-bound paclitaxel]]), developed and manufactured by [http://www.abraxisbio.com Abraxis BioScience], for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. In this preparation, paclitaxel is bonded to [[Human serum albumin|albumin]] as the delivery agent as an alternative to the often toxic solvent delivery method of 'Taxol'.<ref name="paclitaxel">"[http://www.fda.gov/cder/foi/label/2005/021660lbl.pdf paclitaxel Drug Information]." ''[[Food and Drug Administration]].'' [[January 7]], [[2005]]. Retrieved on [[March 9]], [[2007]].</ref> Numerous other Taxol administration techniques are also currently being researched, in an effort to reduce the side effects of Taxol treatment, and increase its effectiveness.
The closely related taxane [[docetaxel]] has a similar set of clinical uses to paclitaxel. It is manufactured under a name of Taxotere.
===Restenosis===
Paclitaxel is used for the prevention of [[restenosis]] (recurrent narrowing) of coronary [[stent]]s; locally delivered to the wall of the [[coronary artery]], a paclitaxel coating limits the growth of neointima (scar tissue) within stents.<ref name=Heldman>{{cite journal | author = Heldman A, Cheng L, Jenkins G, Heller P, Kim D, Ware M, Nater C, Hruban R, Rezai B, Abella B, Bunge K, Kinsella J, Sollott S, Lakatta E, Brinker J, Hunter W, Froehlich J | title = Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. | journal = Circulation | volume = 103 | issue = 18 | pages = 2289-95 | year = 2001 | pmid=11342479}}</ref> Paclitaxel [[drug-eluting stent|drug eluting coated stents]] are sold under the trade name Taxus by [[Boston Scientific]] in the United States.
===Side Effects===
Common side-effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting 2-3 days, changes in the color of the nails, tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at the injection site, change in normal bowel habits for more than 2 days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing and chest pain can also occur. A number of these side effects are associated with the [[excipient]] used, [[Cremophor EL]], a polyoxyethylated [[castor oil]]. Allergies to drugs such as cyclosporine, teniposide and drugs containing polyoxyethylated castor oil may indicate increased risk of adverse reactions to paclitaxel. [[Dexamethasone]] is given prior to beginning paclitaxel treatment to mitigate some of the side effects.<ref name="medline">"[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a698035.html Medline Plus Entry for Taxol]." ''[[MEDLINE]].'' Last revised on [[April 1]], [[2003]]. Retrieved on [[March 9]], [[2007]].</ref>
In recent years, extensive research has been done to find a way to mitigate the side effects of paclitaxel, by altering its administration. DHA-paclitaxel, PG-paclitaxel, and tumor-activated Taxol prodrugs are undergoing continued testing, and are actually on the way to being introduced into widespread clinical use. ''Drug Discovery Today'' reported that Protarga has linked paclitaxel to docosahexaenoic acid, a fatty acid that is easily taken up by tumor cells; the DHA-paclitaxel “appears not to be cytotoxic until the bond with DHA [docosahexaenoic acid] is cleaved within the cell.”<ref>Whelan, Jo. ''Drug Discovery Today'', Volume 7, Issue 2, 15 January 2002, Pages 90-92.</ref> The advantage of DHA-paclitaxel over paclitaxel is DHA-paclitaxel’s ability to carry much higher concentrations of paclitaxel to the cells, which are maintained for longer periods in the tumor cells, thus increasing their action. With increased activity, DHA-paclitaxel, also known as Taxoprexin® may have a more successful response in cancer patients than Taxol, and it may be able to treat more types of cancer than Taxol has been able to treat. ''Drug Discovery Today'' announced that Cell Therapeutics has formulated PG-paclitaxel, which is paclitaxel bonded to a polyglutamate polymer; tumor cells are significantly more porous to polyglutamate polymers than normal cells, due to the leaky endothelial membranes of tumor cells. PG-paclitaxel has been introduced into clinical use, and has proven to initiate very mild side effects and to effectively treat many patients who were not responsive to the action of Taxol. The PG-paclitaxel may be a very promising anti-cancer drug, as it is much more selective than paclitaxel for which cells it targets.<ref>Whelan, Jo. ''Drug Discovery Today'', Volume 7, Issue 2, 15 January 2002, Pages 90-92.</ref> ImmunoGen has been introducing Tumor-Activated Prodrug (TAP™) technology in recent years, and is now working to apply this technology to paclitaxel. Tumor-activated Taxol prodrugs are designed for accurate targeting, by the action of a monoclonal antibody which is very specific to certain cells. Tumor-Activated Taxol prodrugs research is progressing, and in mice, the “taxane-based TAP completely eradicated human tumour xenografts at non-toxic doses.”<ref>Whelan, Jo. ''Drug Discovery Today'', Volume 7, Issue 2, 15 January 2002, Pages 90-92.</ref> Taxol research is dramatically growing, as scientists are working to find cures for the terrible cancers that are affecting so many people in the world today.
==Research use==
Aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a [[microtubule]] stabilizer. [[In vitro]] assays involving microtubules, such as [[motility assay]]s, generally rely on paclitaxel to maintain microtubule integrity in the absence of the various nucleating factors and other stabilizing elements found in the cell. For example, it is used for in vitro tests of drugs that aim to alter the behavior of microtubule [[motor proteins]], or for studies of mutant motor proteins. Paclitaxel is sometimes used for [[in vivo]] studies as well; it can be fed to test organisms such as [[fruit flies]] or injected into individual cells, to inhibit microtubule disassembly or to increase the number of microtubules in the cell.
==Additional images==
<gallery>
Image:Taxol.jpg|Model of the Paclitaxel molecule
Image:Taxol.gif|Rotated Paclitaxel molecule model (Animated GIF, 1.2Mb size)
</gallery>
==References==
{{Reflist|2}}
==External links==
*[http://www.cancer.gov/cancertopics/druginfo/paclitaxel NCI Drug Information Summary for Patients].
*[http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39762 NCI Drug Dictionary Definition]
* [http://www.bris.ac.uk/Depts/Chemistry/MOTM/taxol/taxol2.htm ''Molecule of the Month: TAXOL''] by Neil Edwards, [[University of Bristol]].
* [http://www.research.fsu.edu/researchr/fall2002/taxol.html ''A Tale of Taxol''] from [[Florida State University]].
*[http://www.virtualcancercentre.com/drugs.asp?drugid=1695 Anzatax / Paclitaxel] Virtual Cancer Centre
*{{cite news | url = http://query.nytimes.com/gst/fullpage.html?sec=health&res=9B0CE1DD1730F932A35753C1A9609C8B63&partner=rssnyt&emc=rss} | title = Hope, at $4,200 a Dose | last = Berenson | first = Alex | date = October 1, 2006 | accessdate = 2007-03-31 | publisher = [[The New York Times]]}}
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Black Box Warning
Neutropenia
See full prescribing information for complete Boxed Warning.
* Do not administer paclitaxel therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
Overview
Paclitaxel is a mitotic inhibitor that is FDA approved for the treatment of metastatic breast cancer, non-small cell lung cancer and adenocarcinoma of the pancreas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, diarrhea, inflammatory disease of mucous membrane, nausea and vomiting, any grade of anemia, leukopenia, any grade of neutropenia, any grade of thrombocytopenia, any grade of hypersensitivity reaction, arthralgia, myalgia and peripheral neuropathy..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Metastatic Breast Cancer
Paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
Dosage: 260 mg/m2 administered intravenously over 30 minutes every 3 weeks
Non-Small Cell Lung Cancer
Paclitaxel is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
Dosage: 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle.
Administer carboplatin on Day 1 of each 21 day cycle immediately after paclitaxel
Adenocarcinoma of the Pancreas
Paclitaxel is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
Dosage: 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.
Administer gemcitabine immediately after paclitaxel on Days 1, 8 and 15 of each 28-day cycle
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in adult patients.
Non–Guideline-Supported Use
Angiosarcoma
Breast cancer
Cancer of unknown origin
Carcinoma of bladder
Carcinoma of esophagus
In combination with carboplatin or cisplatin in carcinoma of fallopian tube
Carcinoma of prostate
Cervical cancer
Gastric cancer
Head and neck cancer
Malignant lymphoma
Malignant neoplasm of endometrium of corpus uteri
Malignant tumor of nasopharynx
In combination with carboplatin or cisplatin in malignant tumor of peritoneum
Multiple myeloma of ovarian origin
Non-small cell lung cancer
Non-small cell lung cancer, First-line treatment in combination with bevacizumab and carboplatin for advanced/metastatic non-squamous cell disease
Oligodendroglioma of brain
Ovarian cancer
Small cell carcinoma of lung
Testicular cancer
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Paclitaxel FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Paclitaxel in pediatric patients.
Contraindications
Paclitaxel should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
Patients who experience a severe hypersensitivity reaction to paclitaxel should not be rechallenged with the drug.
Warnings
Neutropenia
See full prescribing information for complete Boxed Warning.
* Do not administer paclitaxel therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
Hematologic Effects
Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel.
In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer).
Do not administer paclitaxel to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of paclitaxel therapy, reduce the dose of paclitaxel in subsequent courses in patients with either MBC or NSCLC.
In patients with MBC, resume treatment with every-3-week cycles of paclitaxel after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly paclitaxel and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle.
In patients with adenocarcinoma of the pancreas, withhold paclitaxel and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended.
Nervous System
Sensory neuropathy is dose- and schedule-dependent.
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification.
If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of paclitaxel
Sepsis
Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis.
If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics.
For febrile neutropenia, interrupt paclitaxel and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels.
Pneumonitis
Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel in combination with gemcitabine.
Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel and gemcitabine.
5.5 Hypersensitivity
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to paclitaxel should not be re-challenged with this drug.
Albumin (Human)
Paclitaxel contains albumin (human). Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases
A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.
No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Adverse Reactions
Clinical Trials Experience
The most common adverse reactions (≥ 20%) with single-agent use of paclitaxel in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.
The most common adverse reactions (≥ 20%) of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue.
The most common serious adverse reactions of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%).
The most common adverse reactions resulting in permanent discontinuation of paclitaxel are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%).
The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (24%), thrombocytopenia (13%), and anemia (6%).
The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
In a randomized open-label trial of paclitaxel in combination with gemcitabine for pancreatic adenocarcinoma, the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of paclitaxel are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.
The most common serious adverse reactions of paclitaxel (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%).
The most common adverse reactions resulting in permanent discontinuation of paclitaxel are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%).
The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (10%) and peripheral neuropathy (6%).
The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
Postmarketing Experience
Hypersensitivity Reactions
Severe and sometimes fatal hypersensitivity reactions have been reported with paclitaxel. The use of paclitxel in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
Cardiovascular
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with paclitaxel.
Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.
Respiratory
There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving paclitaxel and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.
Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with paclitaxel.
Neurologic
Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
Vision Disorders
Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.
Reduced visual acuity due to cystoid macular edema (CME)
After cessation of treatment, CME improves and visual acuity may return to baseline.
Hepatic
Reports of hepatic necrosis and hepatic encephalopathy leading to death
Gastrointestinal
Intestinal obstruction
Intestinal perforation
Pancreatitis
Ischemic colitis
Neutropenic enterocolitis (typhlitis)
Injection Site Reaction
Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety.
In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.
Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
Other Clinical Events
Skin reactions including generalized or maculopapular rash, erythema, and pruritus.
Photosensitivity reactions
Radiation recall phenomenon
In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported
Conjunctivitis
Cellulitis
Increased lacrimation
Drug Interactions
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.
Caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): D
There are no adequate and well-controlled studies in pregnant women using paclitaxel. Based on its mechanism of action and findings in animals, paclitaxel can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving paclitaxel.
Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paclitaxel in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Paclitaxel during labor and delivery.
Nursing Mothers
It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of paclitaxel in pediatric patients have not been evaluated.
Geriatic Use
Of the 229 patients in the randomized study who received paclitaxel for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received paclitaxel.
Of the 514 patients in the randomized study who received paclitaxel and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.
Of the 431 patients in the randomized study who received paclitaxel and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of paclitaxel did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Paclitaxel with respect to specific gender populations.
Race
There is no FDA guidance on the use of Paclitaxel with respect to specific racial populations.
Renal Impairment
Adjustment of the starting paclitaxel dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥30 to <90 mL/min).
There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min).
Hepatic Impairment
Hepatic Impairment
Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of paclitaxel in patients with hepatic impairment should be performed with caution.
Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.
Paclitaxel is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, paclitaxel is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment.
Females of Reproductive Potential and Males
Men should be advised not to father a child while receiving paclitaxel.
Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
Immunocompromised Patients
There is no FDA guidance one the use of Paclitaxel in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
There is limited information regarding Paclitaxel Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Paclitaxel and IV administrations.
Overdosage
There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Structure
The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.91.
Pharmacodynamics
There is limited information regarding Paclitaxel Pharmacodynamics in the drug label.
Pharmacokinetics
Absorption
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of paclitaxel at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of paclitaxel for paclitaxel were independent of the duration of intravenous administration.
Distribution
Paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.
Metabolism
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.
Elimination
At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.
After a 30-minute infusion of 260 mg/m2 doses of paclitaxel, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.
Fecal excretion was approximately 20% of the total dose administered.
Nonclinical Toxicology
The carcinogenic potential of paclitaxel has not been studied.
Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice).
Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis).
Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m2 in rodents and 175 mg/m2 in dogs.
Clinical Studies
14.1 Metastatic Breast Cancer
Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of paclitaxel in metastatic breast cancer.
Single Arm Open Label Studies
In one study, paclitaxel was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m2 as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.
Randomized Comparative Study
This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive paclitaxel at a dose of 260 mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
In this trial, patients in the paclitaxel treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. There was no statistically significant difference in overall survival between the two study arms.
How Supplied
There is limited information regarding Paclitaxel How Supplied in the drug label.
Storage
There is limited information regarding Paclitaxel Storage in the drug label.
Images
Drug Images
{{#ask: Page Name::Paclitaxel
|?Pill Name
|?Drug Name
|?Pill Ingred
|?Pill Imprint
|?Pill Dosage
|?Pill Color
|?Pill Shape
|?Pill Size (mm)
|?Pill Scoring
|?NDC
|?Drug Author
|format=template
|template=DrugPageImages
|mainlabel=-
|sort=Pill Name
}}
3D.png){kind=link}
