Pharmacodynamics
Compared with placebo, there was a significant difference in favor of Xofigo for all five serum biomarkers for bone turnover studied in a phase 2 randomized 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 [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]).

Pharmacokinetics
The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose proportionality and time independence in the dose range investigated (46 to 250 kBq [1.24 to 6.76 microcurie] per kg body weight).

Distribution
After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is excreted into intestine. Fifteen minutes post-injection, about 20% of the injected radioactivity remained in blood. At 4 hours, about 4% of the injected radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection. At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the 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 [see Dosage and Administration (2.3)].

Metabolism
Radium-223 is an isotope that decays and is not metabolized.

Elimination
Special Populations
Pediatric patients
Safety and effectiveness of Xofigo have not been established in children and adolescents below 18 years of age.

Patients with hepatic impairment
No dedicated pharmacokinetic study in patients with hepatic impairment has been conducted. However, since radium-223 is not metabolized and there is no evidence of hepato-biliary excretion based on imaging data, hepatic impairment is not expected to affect the pharmacokinetics of radium-223 dichloride.

Patients with renal impairment
No dedicated pharmacokinetic study in patients with renal impairment has been conducted. However, since excretion in urine is minimal and the major route of elimination is via the feces, renal impairment is not expected to affect the pharmacokinetics of radium-223 dichloride.

Cardiac Electrophysiology
The effect of a single dose of 50 kBq/kg of radium-223 dichloride on the QTc interval was eva luated in a subgroup of 29 patients (21 received Xofigo and 8 received placebo) in the randomized clinical trial. No large changes in the mean QTc interval (i.e., greater than 20 ms) were detected up to 6 hours post-dose. The potential for delayed effects on the QT interval after 6 hours was not eva luated.

Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to eva luate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinic