Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer
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223Ra-Dichloride (223Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent.
Ten patients received either 50, 100, or 200 kBq of 223Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed.
Pharmacokinetic studies showed rapid clearance of 223Ra from the vasculature, with a median of 14 % (range 9–34 %), 2 % (range 1.6–3.9 %), and 0.5 % (range 0.4–1.0 %) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52 % of administered 223Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4 % of administered 223Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients.
223Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.
KeywordsBone metastases Prostate cancer 223Ra Radium Radionuclide therapy Alpharadin
Thanks to the expertise of our research study assistant, Christina Hong, Lauren Borwick, and Ernest Flatts; Research Nurse: Amabella B. Lindo, and Louise B. Harris and our Nuclear Medicine technologists. Support: Algeta ASA
Conflicts of interest
Jorge A. Carrasquillo, John L. Humm and Joseph A. O’Donoghue consult for Algeta ASA. Anne-Kirsti Aksnes is an employee of Algeta ASA. All other authors declare they have no conflict of interest.
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