radium-223
{{Short description|Isotope of radium}}
{{Use dmy dates|date=August 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox isotope
| alternate_names = actinium X, AcX
| symbol = Ra
| mass_number = 223
| mass = 223.0185007(22)
| num_neutrons = 135
| num_protons = 88
| abundance =
| halflife = {{val|11.43|0.05|u=days}}
| image =
| image_caption = image caption
| decay_product = radon-219
| decay_symbol = 219Rn
| decay_mass =
| decay_mode1 = α
| decay_energy1 = 5.979{{AME2016 II|ref|name-list-style = vanc }}
| decay_mode2 =
| decay_energy2 =
| decay_mode3 =
| decay_energy3 =
| decay_mode4 =
| decay_energy4 =
| parent = thorium-227
| parent_symbol = 227Th
| parent_mass =
| parent_decay =
| parent2 = francium-223
| parent2_symbol = 223Fr
| parent2_mass =
| parent2_decay =
| spin =
| excess_energy =
| binding_energy =
}}
Radium-223 (223Ra, Ra-223) is an isotope of radium with an 11.4-day half-life. It was discovered in 1905 by T. Godlewski,{{cite journal| vauthors = Godlewski T |title=A new radio-active product from actinium |journal=Nature |volume=71 |issue=1839 |year=1905 |pages=294–295 |issn=0028-0836 |doi=10.1038/071294b0|bibcode=1905Natur..71..294G|s2cid=4047285 |url=https://zenodo.org/record/2115992}}{{cite journal| vauthors = Godlewski T |title=V. Actinium and its successive products|journal=The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science|volume=10|issue=55|year=1905|pages=35–45|issn=1941-5982|doi=10.1080/14786440509463342|url=https://zenodo.org/record/2216022}}{{cite journal| vauthors = Hahn O |title=A new product of actinium|journal=Nature|volume=73|issue=1902|year=1906|pages=559–560|issn=0028-0836|doi=10.1038/073559b0|bibcode=1906Natur..73..559H|s2cid=4052127 |url=https://zenodo.org/record/1705916}} a Polish chemist from Kraków, and was historically known as actinium X (AcX).{{cite journal | vauthors = Kirby HW |title=The discovery of actinium |year=1971 |journal=Isis |volume=62 |issue=3 |pages=290–308 |doi =10.1086/350760 |jstor=229943 |s2cid=144651011 }}{{cite journal| vauthors = Fry C, Thoennessen M |title=Discovery of actinium, thorium, protactinium, and uranium isotopes|journal=Atomic Data and Nuclear Data Tables|volume=99|issue=3|year=2013|pages=345–364|issn=0092-640X|doi=10.1016/j.adt.2012.03.002|bibcode=2013ADNDT..99..345F|arxiv=1203.1194|s2cid=97142872}} Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover.{{Cite book|title=Medical-Surgical Nursing: Assessment and Management of Clinical Problems | edition = 10th | vauthors = Lewis SL, Bucher L, Heitkemper M, Harding MM |publisher=Elsevier|year=2017|isbn=978-0-323-32852-4}} The principal use of radium-223, as a radiopharmaceutical to treat metastatic cancers in bone, takes advantage of its chemical similarity to calcium, and the short range of the alpha radiation it emits.{{cite journal | vauthors = Marques IA, Neves AR, Abrantes AM, Pires AS, Tavares-da-Silva E, Figueiredo A, Botelho MF | title = Targeted alpha therapy using Radium-223: From physics to biological effects | journal = Cancer Treatment Reviews | volume = 68 | pages = 47–54 | date = July 2018 | pmid = 29859504 | doi = 10.1016/j.ctrv.2018.05.011 | s2cid = 44144271 }}
Origin and preparation
Although radium-223 is naturally formed in trace amounts by the decay of uranium-235, it is generally made artificially,Bruland O.S., Larsen R.H. (2003). Radium revisited. In: Bruland O.S., Flgstad T., editors. Targeted cancer therapies: An odyssey. University Library of Tromso, Ravnetrykk No. 29. {{ISBN|82-91378-32-0}}, pp. 195–202. [http://www.bruland.info/PDF/195-202.pdf] {{Webarchive|url=https://web.archive.org/web/20160421060024/http://www.bruland.info/PDF/195-202.pdf |date=21 April 2016 }} by exposing natural radium-226 to neutrons to produce radium-227, which decays with a 42-minute half-life to actinium-227. Actinium-227 (half-life 21.8 years) in turn decays via thorium-227 (half-life 18.7 days) to radium-223. This decay path makes it convenient to prepare radium-223 by "milking" it from an actinium-227 containing generator or "cow", similar to the moly cows widely used to prepare the medically important isotope technetium-99m.
223Ra itself decays to 219Rn (half-life 3.96 s), a short-lived gaseous radon isotope, by emitting an alpha particle of 5.979 MeV.{{AME2016 II|ref|name-list-style = vanc}}
Medical uses
{{Infobox drug
| drug_name = Radium-223 chloride
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477348686
| image =
| alt =
| caption =
| tradename = Xofigo
| Drugs.com = {{Drugs.com|cons|xofigo}}
| MedlinePlus =
| DailyMedID = Xofigo
| pregnancy_AU =
| pregnancy_category=
| routes_of_administration = Intravenous
| ATC_prefix = V10
| ATC_suffix = XX03
| legal_AU = S4
| legal_CA =
| legal_UK =
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_status =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 444811-40-9
| PubChem = 6335825
| ChEBI = 74895
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = none
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = RJ00KV3VTG
| KEGG = D10398
| IUPAC_name = Radium-223 chloride
| chemical_formula = 223RaCl2
| molecular_weight = 296.91
| molecular_weight_comment = g/mol
}}
The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland"Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning" US 6635234 and has been developed by the former Norwegian company Algeta ASA, in a partnership with Bayer, under the trade name Xofigo (formerly Alpharadin), and is distributed as a solution containing radium-223 chloride (1100 kBq/ml), sodium chloride, and other ingredients for intravenous injection. Algeta ASA was later acquired by Bayer who is the sole owner of Xofigo.{{cite web |title=Xofigo Summary of Product Characteristics |url=https://www.ema.europa.eu/en/documents/product-information/xofigo-epar-product-information_en.pdf |website=European Medicines Authority |publisher=Bayer |access-date=9 October 2019 |date=11 October 2018}}
= Mechanism of action =
{{see also|Targeted alpha-particle therapy}}
The use of radium-223 to treat metastatic bone cancer relies on the ability of alpha radiation from radium-223 and its short-lived decay products to kill cancer cells. Radium is preferentially absorbed by bone by virtue of its chemical similarity to calcium, with most radium-223 that is not taken up by the bone being cleared, primarily via the gut, and excreted.{{cite journal | vauthors = Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS | display-authors = 6 | title = First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases | journal = Clinical Cancer Research | volume = 11 | issue = 12 | pages = 4451–9 | date = June 2005 | pmid = 15958630 | doi = 10.1158/1078-0432.CCR-04-2244 | s2cid = 72948306 | doi-access = }} Although radium-223 and its decay products also emit beta and gamma radiation, over 95% of the decay energy is in the form of alpha radiation.{{cite journal | vauthors = Bruland ØS, Nilsson S, Fisher DR, Larsen RH | title = High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? | journal = Clinical Cancer Research | volume = 12 | issue = 20 Pt 2 | pages = 6250s–6257s | date = October 2006 | pmid = 17062709 | doi = 10.1158/1078-0432.CCR-06-0841 | doi-access = | s2cid = 21171264 }} Alpha radiation has a very short range in tissues compared to beta or gamma radiation: around 2–10 cells. This reduces damage to surrounding healthy tissues, producing an even more localized effect than the beta-emitter strontium-89, also used to treat bone cancer.{{cite journal | vauthors = Henriksen G, Fisher DR, Roeske JC, Bruland ØS, Larsen RH | title = Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice | journal = Journal of Nuclear Medicine | volume = 44 | issue = 2 | pages = 252–9 | date = February 2003 | pmid = 12571218 | url = http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=12571218 }} Taking account of its preferential uptake by bone and the alpha particles' short range, radium-223 is estimated to give targeted osteogenic cells a radiation dose at least eight times higher than other non-targeted tissues.
= Clinical trials and FDA and EMA approval =
The phase II study of radium-223 in castration-resistant prostate cancer (CRPC) patients with bone metastases showed minimum myelotoxicity and good tolerance for the treatment.{{cite journal | vauthors = Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS | display-authors = 6 | title = Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study | journal = The Lancet. Oncology | volume = 8 | issue = 7 | pages = 587–94 | date = July 2007 | pmid = 17544845 | doi = 10.1016/S1470-2045(07)70147-X }}
223Ra successfully met the primary endpoint of overall survival in the phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) study for bone metastases resulting from CRPC in 922 patients.
The ALSYMPCA study was stopped early after a pre-planned efficacy interim analysis, following a recommendation from an Independent Data Monitoring Committee, on the basis of achieving a statistically significant improvement in overall survival (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for 223Ra and 11.2 months for placebo).[http://prostatecancerinfolink.net/2011/09/26/full-data-report-from-the-alsympca-trial-of-radium-223-presented/ Full data report from the ALSYMPCA trial of radium-223 presented] Earlier phase II of the trial showed a median increased survival of 18.9 weeks (around 4.4 months). The lower figure of 2.8 months increased survival in interim phase III results is a probable result of stopping the trial; median survival time for patients still alive could not be calculated. A 2014 update indicates a median increased survival of 3.6 months.{{cite journal | vauthors = Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wichno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Volgelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O | display-authors = 6 | title = Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer | journal = New England Journal of Medicine | volume = 369 | issue = 3 | pages = 213–223 | date = 18 July 2013 | pmid = 23863050 | doi = 10.1056/NEJMoa1213755| doi-access = free }}
In May 2013, 223Ra received marketing approval from the US Food and Drug Administration (FDA){{cite press release |title=FDA approves new drug for advanced prostate cancer |publisher=U.S. Food and Drug Administration (FDA) |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-url=https://web.archive.org/web/20130604012752/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-date=4 June 2013 |url-status=dead |access-date=16 December 2019 }} {{PD-notice}}{{cite web | title=Drug Approval Package: Xofigo (radium Ra 223 dichloride) Injection NDA #203971 | website=U.S. Food and Drug Administration (FDA) | date=21 June 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203971Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20170222064755/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203971Orig1s000TOC.cfm | url-status=dead | archive-date=22 February 2017 | access-date=10 August 2024}} as a treatment for CRPC with bone metastases in people with symptomatic bone metastases and without known visceral disease. 223Ra received priority review as a treatment for an unmet medical need, based on its ability to extend overall survival as shown its Phase III trial.
This study also led to approval in the European Union in November 2013,{{Cite web| url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002653/human_med_001692.jsp&mid=WC0b01ac058001d124| title=Xofigo| date=17 September 2018| access-date=3 September 2015| archive-date=19 August 2018| archive-url=https://web.archive.org/web/20180819182318/http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002653/human_med_001692.jsp&mid=WC0b01ac058001d124| url-status=dead}} The European Medicines Agency subsequently recommended restricting its use to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments. The medicine must also not be used with abiraterone acetate, prednisone or prednisolone and its use is not recommended in patients with a low number of osteoblastic bone metastases.{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/xofigo|title=EMA restricts use of prostate cancer medicine Xofigo |date=28 September 2018|website=European Medicines Agency}}
223Ra also showed promising preliminary results in a phase IIa trial enrolling 23 women with bone metastases resulting from breast cancer that no longer responds to endocrine therapy.{{cite journal | vauthors = Coleman R, Aksnes AK, Naume B, Garcia C, Jerusalem G, Piccart M, Vobecky N, Thuresson M, Flamen P | display-authors = 6 | title = A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease | journal = Breast Cancer Research and Treatment | volume = 145 | issue = 2 | pages = 411–418 | date = June 2014 | pmid = 24728613 | pmc = 4025174 | doi = 10.1007/s10549-014-2939-1 | doi-access = free }} 223Ra treatment reduced the levels of bone alkaline phosphatase (bALP) and urine N-telopeptide (uNTX), key markers of bone turnover associated with bone metastases in breast cancer, diminished bone pain slightly though consistently, and was well tolerated. Another single-arm, open-label Phase II trial reported possible efficacy of 223Ra combined with endocrine therapy in hormone-receptor-positive, bone-dominant breast cancer metastasis.{{cite journal | vauthors = Ueno NT, Tahara RK, Fujii T, Reuben JM, Gao H, Saigal B, Lucci A, Iwase T, Ibrahim NK, Damodaran S, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Lim B, Chasen BA | display-authors = 6 | title = Phase II study of Radium-223 dichloride combined with hormonal therapy for hormone receptor-positive, bone-dominant metastatic breast cancer | journal = Cancer Medicine | volume = 9 | issue = 3 | pages = 1025–1032 | date = February 2020 | pmid = 31849202 | pmc = 6997080 | doi = 10.1002/cam4.2780 | doi-access = free }}
=Side effects=
The most common side effects reported during clinical trials in men receiving 223Ra were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.
=Other radium-223-based compounds=
Although radium does not easily form stable molecular complexes,{{cite journal | vauthors = Henriksen G, Hoff P, Larsen RH | title = Evaluation of potential chelating agents for radium | journal = Applied Radiation and Isotopes | volume = 56 | issue = 5 | pages = 667–71 | date = May 2002 | pmid = 11993940 | doi = 10.1016/s0969-8043(01)00282-2 | bibcode = 2002AppRI..56..667H }} data has been presented on methods to increase and customize its specificity for particular cancers by linking it to monoclonal antibodies, by enclosing the 223Ra in liposomes bearing the antibodies on their surface.{{cite journal | vauthors = Henriksen G, Schoultz BW, Michaelsen TE, Bruland ØS, Larsen RH | title = Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides | journal = Nuclear Medicine and Biology | volume = 31 | issue = 4 | pages = 441–9 | date = May 2004 | pmid = 15093814 | doi = 10.1016/j.nucmedbio.2003.11.004 }}
References
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Category:Drugs developed by Bayer
Category:Drugs acting on the musculoskeletal system