166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.
166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical.


METHODS
After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model.


RESULTS
In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose.


CONCLUSIONS
Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.
Breitz
Hazel B
HB
NeoRx Corp., Seattle, Washington 98119-4115, USA. hbreitz@neorx.com
Wendt
Richard E
RE
Stabin
Michael S
MS
Shen
Sui
S
Erwin
William D
WD
Rajendran
Joseph G
JG
Eary
Janet F
JF
Durack
Lawrence
L
Delpassand
Ebrahim
E
Martin
William
W
Meredith
Ruby F
RF
D000368:Aged; D001822:Body Burden; D001859:Bone Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D005260:Female; D006695:Holmium / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000532:radiotherapy*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D012062:Relative Biological Effectiveness; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014915:Whole-Body Counting / Q000379:methods*
D009943:Organophosphorus Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C082084:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid); D006695:Holmium