Doxorubicin
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Pronunciation | /ˌdɒksəˈruːbɪsɪn/ |
Trade names | Adriamycin, Caelyx,[1] Myocet,[2] others |
Biosimilars | Zolsketil pegylated liposomal,[3] Celdoxome pegylated liposomal[4] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682221 |
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intravesical | |
ATC code | |
Legal status | |
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Pharmacokinetic data | |
Bioavailability | 5% (by mouth) |
Protein binding | 75%[8] |
Metabolism | Liver |
Elimination half-life | Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours[8][9] |
Excretion | Urine (5–12%), faeces (40–50%)[8] |
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Doxorubicin, sold under the brand name Adriamycin among others, is a
Common side effects include
Doxorubicin was approved for medical use in the United States in 1974.
Medical uses
In the EU doxorubicin pegylated liposomal (as Caelyx) is
Doxorubicin is commonly used to treat some
Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after
Side effects
Cardiotoxicity
The most dangerous side effect of doxorubicin is
Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged.[19] This results in both systolic and diastolic dysfunction.[19] Eventually, heart failure can result, which carries a 50% mortality rate.[19] There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.[19] The drug dexrazoxane may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.[20]
Other
Another common and potentially fatal complication of doxorubicin is
Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[25][26]
Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of
Liposomal formulations
There is a
Following administration of this form of doxorubicin, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This liposome-encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.[28][29]
A non-pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for the treatment of metastatic breast cancer in combination with
Biosynthesis
Doxorubicin (DXR) is a 14-
By 1999, they produced recombinant dox A, a
More efficient production techniques have brought the price down to $1.1 million per kg for the non
Mechanism of action
Doxorubicin interacts with DNA by
The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.[37][41]
By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.[42][43] As a result, the DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.[42]
History
In the 1950s, an Italian research company,
Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.[31] Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.[48]
Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI).[44] In 2016 GPX-150 was granted orphan drug designation by US FDA.[49]
Society and culture
Legal status
On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.[50] The applicant for this medicinal product is Accord Healthcare S.L.U.[50] Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin.[50] It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[50] Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022.[3][51]
On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.[52] The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH.[52] Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979.[52] Celdoxome pegylated liposomal contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[52] Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022.[4]
Names
It is also known as hydroxydaunorubicin and hydroxydaunomycin.[53]
It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.[9]
Formulations
Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.[9] Doxorubicin is also available in liposome-encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and Caelyx,[1] which are also given by intravenous injection.[9]
The FDA approved the first generic version of Doxil, made by Sun, in February 2013.[54]
Research
Further, the release of photo-activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti-cancer effect in MCF-7 breast cancer cells.
Antimalarial activity
There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit
Fluorescence
Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened the possibility of using the molecule as a
References
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- ^ a b c d "Myocet liposomal EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 25 February 2022. Retrieved 20 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b c "Zolsketil pegylated liposomal EPAR". European Medicines Agency (EMA). 24 January 2022. Archived from the original on 21 June 2022. Retrieved 20 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b c "Celdoxome pegylated liposomal EPAR". European Medicines Agency (EMA). 20 June 2022. Retrieved 31 January 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ "Caelyx product information". Health Canada. 25 April 2012. Archived from the original on 21 June 2022. Retrieved 20 June 2022.
- ^ "Myocet product information". Health Canada. 25 April 2012. Retrieved 20 June 2022.
- ^ "Taro-doxorubicin liposomal product information". Health Canada. 25 April 2012. Archived from the original on 14 May 2021. Retrieved 20 June 2022.
- ^ a b c "(doxorubicin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 16 April 2014. Retrieved 15 April 2014.
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- ^ a b c d e f g h i "Doxorubicin Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 11 October 2016. Retrieved 12 January 2017.
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- ^ "Outpatient Oncology Drug Series: Doxorubicin is the Infamous Red Devil". Archived from the original on 21 April 2018. Retrieved 21 April 2018.
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- ^ a b "Liposomal doxorubicin (Caelyx, Myocet)". Macmillan Cancer Support. 1 April 2009. Archived from the original on 29 November 2009. Retrieved 27 November 2009.
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- ^ a b c d "Zolsketil pegylated liposomal: Pending EC decision". European Medicines Agency (EMA). 24 March 2022. Archived from the original on 29 March 2022. Retrieved 29 March 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ "Zolsketil Product information". Union Register of medicinal products. Retrieved 3 March 2023.
- ^ a b c d "Celdoxome pegylated liposomal: Pending EC decision". European Medicines Agency (EMA). 22 July 2022. Archived from the original on 28 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ "Doxorubicin: MedlinePlus Drug Information". medlineplus.gov. Archived from the original on 13 July 2020. Retrieved 12 July 2020.
- ^ "FDA approval of generic version of cancer drug Doxil is expected to help resolve shortage" (Press release). U.S. Food and Drug Administration (FDA). 4 February 2013. Archived from the original on 28 February 2014. Retrieved 22 February 2014.
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External links
- Media related to Doxorubicin at Wikimedia Commons
- "Doxorubicin". Drug Information Portal. U.S. National Library of Medicine.
- "Doxorubicin hydrochloride". Drug Information Portal. U.S. National Library of Medicine.