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

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.