title: Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. carrasj1@mskcc.org
authors: Jorge A
authors: JA
authors: Carrasquillo
authors: Joseph A
authors: JA
authors: O'Donoghue
authors: Neeta
authors: N
authors: Pandit-Taskar
authors: John L
authors: JL
authors: Humm
authors: Dana E
authors: DE
authors: Rathkopf
authors: Susan F
authors: SF
authors: Slovin
authors: Matthew J
authors: MJ
authors: Williamson
authors: Kristine
authors: K
authors: Lacuna
authors: Anne-Kirsti
authors: AK
authors: Aksnes
authors: Steven M
authors: SM
authors: Larson
authors: Howard I
authors: HI
authors: Scher
authors: Michael J
authors: MJ
authors: Morris
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000532:radiotherapy / Q000556:secondary; D004307:Dose-Response Relationship, Radiation; D023381:Endpoint Determination; D006801:Humans; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000532:radiotherapy*; D011868:Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011883:Radium / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C581106:radium Ra 223 dichloride; D011883:Radium
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