Radium Ra 223 Dichloride

Identification

Name
Radium Ra 223 Dichloride
Accession Number
DB08913  (DB05677, DB09566)
Type
Small Molecule
Groups
Approved, Investigational
Description

Radium Ra 223 Dichloride is a radiopharmaceutical containing the radioisotope radium-223 that emits short range but high linear energy alpha particles. As a cation, radium mimics calicum and binds to hydroxyapatite, which is a bone mineral found in areas of high bone turnover as seen in bone metastases. It was first approved by the FDA in May 2013 and is currently marketed under the brand name Xofigo, which was formerly called Alpharadin. Xofigo is indicated in patients who have metastatic bone cancer that is symptomatic with no visceral metastases and patients who have prostate cancer that is castration resistant. The FDA label includes a warning that Radium Ra 223 Dichloride should not be used in women who are pregnant or may become pregnant due to the high risk of fetal harm.

Structure
Thumb
Synonyms
  • RADIUM CHLORIDE RA-223
  • Radium Ra-223 dichloride
  • Radium-223 chloride
  • Radium-223 dichloride
External IDs
BAY 88-8223 / BAY-88-8223 / BAY88-8223
Active Moieties
NameKindUNIICASInChI Key
Radium Ra-223 cationionic9H414A99MDNot AvailablePZDJSXWIQXZUBJ-OIOBTWANSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Radium Ra 223 DichlorideInjection90 uCi/1mLIntravenousCardinal Health 414, Llc2017-06-12Not applicableUs
XofigoInjection30 uCi/1mLIntravenousBayer HealthCare Pharmaceuticals Inc.2013-05-20Not applicableUs
XofigoInjection, solution1100 kBq/mLIntravenousBayer Ag2013-11-13Not applicableEu
International/Other Brands
Alpharadin
Categories
UNII
RJ00KV3VTG
CAS number
444811-40-9
Weight
Average: 293.924
Monoisotopic: 292.956202554
Chemical Formula
Cl2Ra
InChI Key
RWRDJVNMSZYMDV-SIUYXFDKSA-L
InChI
InChI=1S/2ClH.Ra/h2*1H;/q;;+2/p-2/i;;1-3
IUPAC Name
dichloro(223Ra)radium
SMILES
Cl[223Ra]Cl

Pharmacology

Indication

Used in patients who have metastatic bone cancer that is symptomatic with no visceral metastases and patients who have prostate cancer that is castration resistant.

Associated Conditions
Pharmacodynamics

Physiologically, Radium Ra 223 Dichloride, prevents the spread of bone cancer by killing the associated bone cancer cells.

Mechanism of action

Radium Ra 223 Dichloride is the radioisotope radium-223 that emits short range but high linear energy alpha particles. As a cation, radium mimics calicum and binds to hydroxyapatite, which is a bone mineral found in areas of high bone turnover as seen in bone metastases. The high energy damages bone cells by introducing double-stranded DNA breaks. This leads to cell death and prevention of the spread of the bone cancer cells. As well because of the alpha particle's short range of less than 10 cell diameters, its damaging effects would less likely affect the non-cancerous cells nearby.

Absorption

Since Radium Ra 223 Dichloride is administered I.V., the bioavailability should be 100%.

Volume of distribution

The volume of distribution was not quantified, but after 24 hours, there is only 1% radium-223 remaining in the blood. The rest of the radium-223 is distributed to bone (61% of the radioactive dose after 4 hours) and intestine (49% of the radioactive dose after 4 hours). No other organs were found to have significant uptake.

Protein binding

There is negligible plasma protein binding.

Metabolism

Radium-223 does not undergo metabolism because it is a radioisotope that decays.

Route of elimination

Radium-223 is mainly eliminated through the feces (13%) and to a lesser extent in the urine (2%). It is also noted that the elimination rate of radium-223 from the intestines is variable due to the high variability of intestinal transit rates among patients. Therefore there could be more intestinal radiation exposure in patients with slower intestinal transit rates, but the significance of this in relation to toxicity is not known.

Half life

The half-life is relatively long at 11.4 days for radium-223.

Clearance

The clearance rate of radium-223 was not quantified.

Toxicity

Because of its cytotoxic actions that have a high potential to cause fetal harm, Radium Ra 223 Dichloride is contraindicated in women who are pregnant or are of child bearing age. Other side effects include several hematological lab abnormalities, peripheral edema, nausea, vomiting, and diarrhea.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Radium Ra 223 Dichloride.
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Radium Ra 223 Dichloride.
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Radium Ra 223 Dichloride.
CymarinCymarin may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
DeslanosideDeslanoside may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
DigitoxinDigitoxin may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
DigoxinDigoxin may decrease the cardiotoxic activities of Radium Ra 223 Dichloride.
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Radium Ra 223 Dichloride.
Food Interactions
  • Since radium Ra 223 dichloride is administered intravenously, no food effects should occur.

References

General References
  1. Suominen MI, Rissanen JP, Kakonen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Kakonen SM, Scholz A: Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst. 2013 Jun 19;105(12):908-16. doi: 10.1093/jnci/djt116. Epub 2013 May 16. [PubMed:23682134]
  2. Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernas B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS: Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8(7):587-94. [PubMed:17544845]
  3. Bruland OS, Nilsson S, Fisher DR, Larsen RH: High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6250s-6257s. [PubMed:17062709]
External Links
PubChem Substance
175427151
ChemSpider
28528370
ChEBI
74895
ChEMBL
CHEMBL2107816
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Radium-223_chloride
FDA label
Download (552 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCastrate-resistant Prostate Cancer (CRPC)1
1Active Not RecruitingTreatmentMetastatic Renal Cell Carcinoma1
1CompletedNot AvailableBone Diseases / Neoplasms1
1CompletedBasic ScienceMetastases / Pharmacokinetics / Prostate Cancer1
1CompletedBasic ScienceProstatic Neoplasms1
1CompletedTreatmentProstatic Neoplasms1
1, 2Active Not RecruitingTreatmentBone Metastases / Clear-cell Metastatic Renal Cell Carcinoma1
1, 2Active Not RecruitingTreatmentProstatic Neoplasms1
1, 2Active Not RecruitingTreatmentSarcomas1
1, 2CompletedTreatmentBone Metastases / Castration-Resistant Prostate Cancer (CRPC)1
1, 2RecruitingTreatmentMultiple Myeloma (MM)1
1, 2WithdrawnTreatmentMultiple Myeloma (MM)1
2Active Not RecruitingTreatmentCancer, Breast1
2Active Not RecruitingTreatmentNeoplasms, Breast2
2Active Not RecruitingTreatmentNon Small Cell Lung Cancer With Bone Metastatses1
2Active Not RecruitingTreatmentProstate Carcinoma Metastatic to the Bone1
2Active Not RecruitingTreatmentProstatic Neoplasms1
2CompletedTreatmentBone Metastases / Cancer, Breast1
2CompletedTreatmentBone Metastases / Hormone Refractory Prostate Cancer1
2CompletedTreatmentNeoplasms Metastasis / Prostate Cancer2
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentProstatic Neoplasms2
2Enrolling by InvitationBasic ScienceProstate Cancer1
2RecruitingTreatmentCastration-Resistant Prostate Cancer (CRPC) / Castration-resistant Prostate Cancer Metastatic to Bone / Prostate Cancer1
2RecruitingTreatmentProstate Cancer5
2RecruitingTreatmentProstate Cancer Metastatic to Bone1
3Active Not RecruitingTreatmentProstatic Neoplasms1
3CompletedTreatmentBone Metastases / Hormone Refractory Prostate Cancer1
3CompletedTreatmentProstatic Neoplasms2
3RecruitingTreatmentProstate Cancer Metastatic to Bone1
Not AvailableActive Not RecruitingNot AvailableCastration-Resistant Prostatic Cancer1
Not AvailableActive Not RecruitingNot AvailableProstatic Neoplasms1
Not AvailableActive Not RecruitingNot AvailableProstatic Neoplasms, Castration-Resistant3
Not AvailableActive Not RecruitingTreatmentProstate Cancer1
Not AvailableCompletedNot AvailableProstate Cancer1
Not AvailableCompletedNot AvailableProstatic Neoplasms1
Not AvailableCompletedNot AvailableProstatic Neoplasms, Castration-Resistant1
Not AvailableNo Longer AvailableNot AvailableProstatic Neoplasms1
Not AvailableNot Yet RecruitingNot AvailableProstate Cancer, Castration Resistant1
Not AvailableNot Yet RecruitingNot AvailableProstatic Neoplasms1
Not AvailableRecruitingNot AvailableBone Metastases / Metastatic Hormone Refractory Prostate Cancer1
Not AvailableRecruitingNot AvailableBony Metastases From Castrate Refractory Prostate Cancer1
Not AvailableRecruitingNot AvailableCastration resistant / Prostate Cancer / Radium 2231
Not AvailableRecruitingNot AvailableProstatic Neoplasms, Castration-Resistant1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous90 uCi/1mL
InjectionIntravenous30 uCi/1mL
Injection, solutionIntravenous1100 kBq/mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6635234No2000-01-032020-01-03Us

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility74.7 mg/mLALOGPS
logP0.37ALOGPS
logP1.27ChemAxon
logS-0.6ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity12.27 m3·mol-1ChemAxon
Polarizability7.26 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9935
Blood Brain Barrier+0.9786
Caco-2 permeable+0.619
P-glycoprotein substrateNon-substrate0.9022
P-glycoprotein inhibitor INon-inhibitor0.9785
P-glycoprotein inhibitor IINon-inhibitor0.9947
Renal organic cation transporterNon-inhibitor0.9221
CYP450 2C9 substrateNon-substrate0.8005
CYP450 2D6 substrateNon-substrate0.7503
CYP450 3A4 substrateNon-substrate0.7412
CYP450 1A2 substrateNon-inhibitor0.6359
CYP450 2C9 inhibitorNon-inhibitor0.7872
CYP450 2D6 inhibitorNon-inhibitor0.9067
CYP450 2C19 inhibitorNon-inhibitor0.7673
CYP450 3A4 inhibitorNon-inhibitor0.957
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9075
Ames testNon AMES toxic0.7967
CarcinogenicityCarcinogens 0.7993
BiodegradationNot ready biodegradable0.5273
Rat acute toxicity2.4184 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9208
hERG inhibition (predictor II)Non-inhibitor0.9622
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of inorganic compounds known as alkaline earth metal chlorides. These are inorganic compounds in which the largest halogen atom is Chlorine, and the heaviest metal atom is a lanthanide.
Kingdom
Inorganic compounds
Super Class
Mixed metal/non-metal compounds
Class
Alkaline earth metal salts
Sub Class
Alkaline earth metal chlorides
Direct Parent
Alkaline earth metal chlorides
Alternative Parents
Inorganic chloride salts
Substituents
Alkaline earth metal chloride / Inorganic chloride salt / Inorganic salt
Molecular Framework
Not Available
External Descriptors
inorganic chloride, radium molecular entity (CHEBI:74895)

Drug created on June 26, 2013 21:05 / Updated on August 02, 2018 06:11