Chemical formula: Ra Molecular mass: 293.924 g/mol
Radium-223 dichloride is a therapeutic alpha particle-emitting pharmaceutical.
Radium-223 dichloride mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters (80 keV/µm) leads to a high frequency of double-strand DNA breaks in adjacent tumour cells, resulting in a potent cytotoxic effect. Additional effects on the tumour microenvironment including osteoblasts and osteoclasts also contribute to the in vivo efficacy. The alpha particle range from radium-223 is less than 100 µm (less than 10 cell diameters) which minimises damage to the surrounding normal tissue.
Compared with placebo, there was a significant difference in favour of radium-223 dichloride for all five serum biomarkers for bone turnover studied in a phase II randomised study (bone formation markers: bone alkaline phosphatase [ALP], total ALP and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen/serum C-terminal crosslinked telopeptide of type I collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]).
No significant QTc prolonging effects were observed after intravenous injection of radium-223 dichloride in comparison with placebo in a subgroup of 29 patients in the phase III study (ALSYMPCA).
Pharmacokinetic, biodistribution and dosimetry data have been obtained from 3 phase I studies. Pharmacokinetic data were obtained in 25 patients at activities ranging from 51 to 276 kBq/kg. Pharmacokinetic, biodistribution and dosimetry data were obtained in 6 patients at an activity of 110 kBq/kg given twice, 6 weeks apart, and in 10 patients at an activity of 55, 110 or 221 kBq/kg.
Radium-223 dichloride is administered as an intravenous injection and is thus 100% bioavailable.
After intravenous injection, radium-223 is rapidly cleared from the blood and is incorporated primarily into bone and bone metastases, or is excreted into the intestine.
Fifteen minutes post injection, about 20% of the injected activity remained in the blood. At 4 hours, about 4% of the injected activity remained in the blood, decreasing to less than 1% at 24 hours after the injection. The volume of distribution was higher than the blood volume indicating distribution to peripheral compartments.
At 10 minutes post injection, activity was observed in the bone and in the intestine. At 4 hours post injection, the mean percentage of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively.
No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder and spleen at 4 hours post injection.
Radium-223 is an isotope which decays and is not metabolised.
Faecal excretion is the major route of elimination from the body. About 5% is excreted in the urine and there is no evidence of hepatobiliary excretion.
The whole body measurements at 7 days after injection (after correcting for decay) indicate that a median of 76% of administered activity was excreted from the body. The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population, with the normal range from once daily to once weekly bowel evacuation.
The pharmacokinetics of radium-223 dichloride were linear in the activity range investigated (51 to 276 kBq/kg).
Safety and effectiveness of radium-223 dichloride have not been studied in children and adolescents below 18 years of age.
In single and repeated dose toxicity studies in rats, the main findings were reduced body weight gain, haematological changes, reduced serum alkaline phosphatase and microscopic findings in the bone marrow (depletion of haematopoietic cells, fibrosis), spleen (secondary extra-medullary haematopoiesis) and bone (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganisation of the physis/growth line). These findings were related to radiation-induced impairment of haematopoiesis and a reduction of osteogenesis and started at the lowest activity of 22 kBq per kg body weight (0.4 times the clinically recommended dose).
In dogs, haematological changes were observed starting at the lowest activity of 55 kBq/kg, the clinically recommended dose. Dose-limiting myelotoxicity was seen in dogs after single administration of 497 kBq radium-223 dichloride per kg body weight (9 times the clinically recommended activity).
After repeated administration of the clinically recommended activity of 55 kBq per kg body weight once every 4 weeks for 6 months, two dogs developed non-displaced pelvic fractures. Due to the presence of osteolysis of trabecular bone in other bone locations of treated animals in varying degree, a spontaneous fracture in the context of osteolysis cannot be excluded. The clinical relevance of these findings is unknown.
Retinal detachment was seen in dogs after a single injection of activities of 166 and 497 kBq per kg body weight (3 and 9 times the clinically recommended dose), but not after repeated administration of the clinically recommended activity of 55 kBq per kg body weight once every 4 weeks for 6 months. The exact mechanism for induction of retinal detachment is unknown, but literature data suggests that radium is specifically taken up in the tapetum lucidum of the canine eye. Since humans do not have a tapetum lucidum, the clinical relevance of these findings for humans is uncertain. No case of retinal detachment has been reported in clinical trials.
No histological changes were observed in organs involved in the excretion of radium-223 dichloride.
Osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses in rats 7–12 months after start of treatment. Osteosarcomas were not observed in dog studies. No case of osteosarcoma has been reported in clinical studies with radium-223 dichloride. The risk for patients to develop osteosarcomas with exposure to radium-223 is unknown at present. The presence of neoplastic changes, other than osteosarcomas, was also reported in the longer term (12 to 15 months) rat toxicity studies.
Studies on reproductive and developmental toxicity have not been performed. In general, radionuclides induce reproductive and developmental effects.
A minimal number of abnormal spermatocytes were seen in a few seminiferous tubules in the testes of male rats after a single administration of ≥2270 kBq/kg body weight radium-223 dichloride (≥41 times the clinically recommended activity). The testes seemed to otherwise be functioning normally and the epididymides revealed a normal content of spermatocytes. Uterine polyps (endometrial stroma) were observed in female rats after single or repeated administration of ≥359 kBq/kg body weight radium-223 dichloride (≥6.5 times the clinically recommended activity).
Since radium-223 distributes mainly to bone, the potential risk for adverse effects in the male gonads in cancer patients with castration-resistant prostate cancer is very low, but cannot be excluded.
Studies on the mutagenic and carcinogenic potential of radium-223 dichloride have not been performed. In general, radionuclides are considered to be genotoxic and carcinogenic.
No significant effects were seen on vital organ systems, i.e. cardiovascular (dog), respiratory or central nervous systems (rat), after single dose administration of activities from 497 to 1100 kBq per kg body weight (9 [dog] to 20 [rat] times the clinically recommended activity).
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