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

  • Jorge A. CarrasquilloEmail author
  • Joseph A. O’Donoghue
  • Neeta Pandit-Taskar
  • John L. Humm
  • Dana E. Rathkopf
  • Susan F. Slovin
  • Matthew J. Williamson
  • Kristine Lacuna
  • Anne-Kirsti Aksnes
  • Steven M. Larson
  • Howard I. Scher
  • Michael J. Morris
Original Article



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.


Bone 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.

Supplementary material

259_2013_2427_MOESM1_ESM.docx (252 kb)
ESM 1 (DOCX 252 kb)


  1. 1.
    Keller ET, Zhang J, Cooper CR, Smith PC, McCauley LK, Pienta KJ, et al. Prostate carcinoma skeletal metastases: cross-talk between tumor and bone. Cancer Metastasis Rev 2001;20:333–49. doi: 10.1023/a:1015599831232.PubMedCrossRefGoogle Scholar
  2. 2.
    Weinfurt KP, Li Y, Castel LD, Saad F, Timbie JW, Glendenning GA, et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 2005;16:579–84. doi: 10.1093/annonc/mdi122.PubMedCrossRefGoogle Scholar
  3. 3.
    Agarawal JP, Swangsilpa T, van der Linden Y, Rades D, Jeremic B, Hoskin PJ. The role of external beam radiotherapy in the management of bone metastases. Clin Oncol (R Coll Radiol) 2006;18:747–60. doi: 10.1016/j.clon.2006.09.007.CrossRefGoogle Scholar
  4. 4.
    Lee RJ, Saylor PJ, Smith MR. Contemporary therapeutic approaches targeting bone complications in prostate cancer. Clin Genitourin Cancer 2010;8:29–36. doi: 10.3816/CGC.2010.n.005.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 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
  6. 6.
    Collins C, Eary JF, Donaldson G, Vernon C, Bush NE, Petersdorf S, et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med 1993;34:1839–44.PubMedGoogle Scholar
  7. 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. 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. 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
  10. 10.
    Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 2005;11:4451–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007;8:587–94. doi: 10.1016/s1470-2045(07)70147-x.PubMedCrossRefGoogle Scholar
  12. 12.
    Larsen RH, Saxtorph H, Skydsgaard M, Borrebaek J, Jonasdottir TJ, Bruland OS, et al. Radiotoxicity of the alpha-emitting bone-seeker 223Ra injected intravenously into mice: histology, clinical chemistry and hematology. In Vivo 2006;20:325–31.PubMedGoogle Scholar
  13. 13.
    Henriksen G, Fisher DR, Roeske JC, Bruland ØS, Larsen RH. Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med 2003;44:252–9.PubMedGoogle Scholar
  14. 14.
    Henriksen G, Breistøl K, Bruland ØS, Fodstad Ø, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res 2002;62:3120–5.PubMedGoogle Scholar
  15. 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
  16. 16.
    Skarsgard LD. Radiobiology with heavy charged particles: a historical review. Phys Med 1998;14:1–19.PubMedGoogle Scholar
  17. 17.
    Neuman WF, Hursh JB, Boyd J, Hodge HC. On the mechanism of skeletal fixation of radium. Ann N Y Acad Sci 1955;62:125–36.CrossRefGoogle Scholar
  18. 18.
    Hobbs RF, Song H, Watchman CJ, Bolch WE, Aksnes AK, Ramdahl T, et al. A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol 2012;57:3207–22. doi: 10.1088/0031-9155/57/10/3207.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 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
  20. 20.
    Harrison GE, Carr TEF, Sutton A. Distribution of radioactive calcium, strontium, barium and radium following intravenous injection into a healthy man. Int J Radiat Biol Relat Stud Phys Chem Med 1967;13:235–47.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoecker FE, Roofe PG. Studies of radium in human bone. Radiology 1951;56:89–98.PubMedGoogle Scholar
  22. 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. 23.
    Mays CW, Atherton DR, Christensen WR, Pitchfor G, Lloyd RD. Radium metabolism in a man. Radiat Res 1963;19:210.Google Scholar
  24. 24.
    Nekolla EA, Kellerer AM, Kuse-Isingschulte M, Eder E, Spiess H. Malignancies in patients treated with high doses of radium-224. Radiat Res 1999;152:S3–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Norris WP, Speckman TW, Gustafson PF. Studies of the metabolism of radium in humans. Radiat Res 1954;1:555.Google Scholar
  26. 26.
    Shelley MD, Mason MD. Radium-223 for men with hormone-refractory prostate cancer and bone metastases. Lancet Oncol 2007;8:564–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Tiepolt C, Grüning T, Franke WG. Renaissance of 224Ra for the treatment of ankylosing spondylitis: clinical experiences. Nucl Med Commun 2002;23:61–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Hindorf C, Chittenden S, Aksnes AK, Parker C, Flux GD. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun 2012;33:726–32. doi: 10.1097/MNM.0b013e328353bb6e.PubMedCrossRefGoogle Scholar
  29. 29.
    Bergeron DE, Zimmerman BE, Cessna JT. Development of secondary standards for 223Ra. Appl Radiat Isot 2010;68:1367–70. doi: 10.1016/j.apradiso.2009.11.005.PubMedCrossRefGoogle Scholar
  30. 30.
    Retzlaff JA, Tauxe WN, Kiely JM, Stroebel CF. Erythrocyte volume, plasma volume, and lean body mass in adult men and women. Blood 1969;33:649–61.PubMedGoogle Scholar
  31. 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.
  32. 32.
    Harrison GE, Carr TEF, Sutton A, Rundo J. Plasma concentration and excretion of calcium-47, strontium-85, barium-133 and radium-223 following successive intravenous doses to a healthy man. Nature 1966;209:526–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Looney WB, Archer VE. Radium inhalation accident; radium excretion study. Am J Roentgenol Radium Ther Nucl Med 1956;75:548–58.PubMedGoogle Scholar
  34. 34.
    Salant W, Meyer GM. The elimination of radium in normal and nephrectomized animals. Am J Physiol 1907;20:366–7.Google Scholar
  35. 35.
    Hursh JB, Lovaas A. Biliary excretion of radium in dogs. Health Phys 1960;6:183–8.CrossRefGoogle Scholar
  36. 36.
    Hursh JB, Lovaas A, Piccirilli A, Putnam TE. Urinary excretion of radium in dogs. Am J Physiol 1960;199:513–6.PubMedGoogle Scholar
  37. 37.
    Sansom BF, Garner RJ. The metabolism of radium in dairy cows. Biochem J 1966;99:677–81.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lloyd RD, Mays CW, Taylor GN, Atherton DR, Bruenger FW, Jones CW. Radium-224 retention, distribution, and dosimetry in beagles. Radiat Res 1982;92:280–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Kennel SJ, Lankford T, Garland M, Sundberg JP, Mirzadeh S. Biodistribution of 225Ra citrate in mice: retention of daughter radioisotopes in bone. Nucl Med Biol 2005;32:859–67. doi: 10.1016/j.nucmedbio.2005.05.009.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jorge A. Carrasquillo
    • 1
    • 2
    Email author
  • Joseph A. O’Donoghue
    • 3
  • Neeta Pandit-Taskar
    • 1
    • 2
  • John L. Humm
    • 3
  • Dana E. Rathkopf
    • 4
    • 5
  • Susan F. Slovin
    • 4
    • 5
  • Matthew J. Williamson
    • 3
  • Kristine Lacuna
    • 4
  • Anne-Kirsti Aksnes
    • 6
  • Steven M. Larson
    • 1
    • 2
  • Howard I. Scher
    • 4
    • 5
  • Michael J. Morris
    • 4
    • 5
  1. 1.Molecular Imaging and Therapy Service, Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyWeill Cornell Medical CollegeNew YorkUSA
  3. 3.Department of Medical PhysicsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Genitourinary Oncology Service, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  6. 6.Algeta ASAOsloNorway

Personalised recommendations