Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer
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
- 5.Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–82. doi:10.1093/jnci/djh141.PubMedCrossRefGoogle Scholar
- 7.Porter AT, McEwan AJB, Powe JE, Reid R, McGowan DG, Lukka H, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993;25:805–13.PubMedCrossRefGoogle Scholar
- 8.Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, et al. A randomized, dose–response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer 2012;48:678–86. doi:10.1016/j.ejca.2011.12.023.PubMedCrossRefGoogle Scholar
- 9.Parker C, Heinrich D, Helle SI, O'Sullivan JM, Fossä S, Chodacki A, et al. Overall survival benefit and impact on skeletal-related events for radium-223 chloride (Alpharadin) in the treatment of castration-resistant prostate cancer (CRPC) patients with bone metastases: a phase III randomized trial (ALSYMPCA). Eur Urol Suppl 2012;11:E130–U523.CrossRefGoogle Scholar
- 15.Henriksen G, Hoff P, Alstad J, Larsen RH. 223Ra for endoradiotherapeutic applications prepared from an immobilized 227Ac/227Th source. Radiochim Acta 2001;89:661–6.Google Scholar
- 19.Seil HA, Viol CH, Gordon MA. The elimination of soluble radium salts taken intravenously and per os. N Y Med J 1915;18:896–8.Google Scholar
- 22.Holtzman RB, Lucas HF, Stehney AF. Excretion rates and blood levels of 226Ra and 210Pb in long-term radium-injected patients. Health Phys 1973;25:335.Google Scholar
- 23.Mays CW, Atherton DR, Christensen WR, Pitchfor G, Lloyd RD. Radium metabolism in a man. Radiat Res 1963;19:210.Google Scholar
- 25.Norris WP, Speckman TW, Gustafson PF. Studies of the metabolism of radium in humans. Radiat Res 1954;1:555.Google Scholar
- 31.NCI CTEP. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctepcancergov/protocolDevelopment/electronic_applications/docs/ctcaev3pdf. 2006 ed: National Cancer Institute, NIH; 2006.
- 34.Salant W, Meyer GM. The elimination of radium in normal and nephrectomized animals. Am J Physiol 1907;20:366–7.Google Scholar