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Pharmacokinetics, Dosimetry and Toxicity of Holmium-166-DOTMP for Bone Marrow Ablation in Multiple Myeloma

Departments of Radiation Physics, Nuclear Medicine and Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Research and Development, The Dow Chemical Company, Freeport, Texas

Correspondence: For correspondence or reprints contact: John E. Bayouth, PhD, Department of Radiation Oncology, The University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213.

ABSTRACT

In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. Methods: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (¹⁶⁶Ho) complexed with a bone-seeking agent DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of ¹⁶⁶Ho-DOTMP administered to these myeloma patients was demonstrated from blood(r² = 0.926) and whole-body retention (r²= 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. Results: Over 50% of the ¹⁶⁶Ho-DOTMP injected dose was excreted within 2–3 hr postinjection, increasing to 75%–85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. Conclusion: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/µl), two patients exhibited marrow ablation (WBC count <100 cells/µ), and no other toxicity grade 2 was observed in any of the patients.

Key Words: marrow ablation • radionuclide therapy • marrow dosimetry

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