Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer

Eur J Nucl Med Mol Imaging. 2013 Sep;40(9):1384-93. doi: 10.1007/s00259-013-2427-6. Epub 2013 May 8.

Abstract

Purpose: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Bone Neoplasms / radiotherapy
  • Bone Neoplasms / secondary
  • Dose-Response Relationship, Radiation
  • Endpoint Determination
  • Humans
  • Male
  • Middle Aged
  • Prostatic Neoplasms, Castration-Resistant / radiotherapy*
  • Radioisotopes / adverse effects
  • Radioisotopes / pharmacokinetics
  • Radioisotopes / therapeutic use
  • Radiopharmaceuticals / adverse effects
  • Radiopharmaceuticals / pharmacokinetics*
  • Radiopharmaceuticals / therapeutic use
  • Radium / adverse effects
  • Radium / pharmacokinetics*
  • Radium / therapeutic use
  • Tissue Distribution

Substances

  • Antineoplastic Agents
  • Radioisotopes
  • Radiopharmaceuticals
  • radium Ra 223 dichloride
  • Radium