Breitz Hazel B, Wendt Richard E, Stabin Michael S, Shen Sui, Erwin William D, Rajendran Joseph G, Eary Janet F, Durack Lawrence, Delpassand Ebrahim, Martin William, Meredith Ruby F
NeoRx Corp., Seattle, Washington 98119-4115, USA.
J Nucl Med. 2006 Mar;47(3):534-42.
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.
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.
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.
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.
166Ho-1,4,7,10-四氮杂环十二烷-1,4,7,10-四亚甲基膦酸酯（DOTMP）是一种用166Ho标记的四膦酸酯分子，可定位于骨表面。本研究评估了这种发射β射线的放射性药物的药代动力学以及对所有器官的辐射吸收剂量。
在给予两次1.1GBq的166Ho-DOTMP后，使用γ相机或摄取探头进行全身计数的数据，评估了12例多发性骨髓瘤患者全身滞留的可重复性。使用MIRD方法，应用166Ho的驻留时间和S值，估计正常器官的辐射吸收剂量。根据18小时后测得的滞留活性估计骨髓剂量。确定给予骨髓25Gy治疗剂量所需的活性。评估了基于感兴趣区域（ROI）和全身清除率的方法来估计肾脏活性，因为该放射性示踪剂可迅速经尿液排出。使用动态膀胱模型估计膀胱壁表面的剂量。
在临床实践中，γ相机方法在全身计数方面比基于摄取探头的方法更可靠。两次示踪剂研究之间患者体内剂量计算的变异性小于10%。166Ho-DOTMP的骨骼摄取率在19%至39%之间（平均为28%）。规定用于治疗的166Ho活性范围为38至67GBq（1030-1810mCi）。高剂量治疗后，使用基于全身清除率的方法，肾脏的吸收剂量估计值在1.6至4Gy之间；使用基于ROI的方法，肾脏的吸收剂量估计值在8.3至17.3Gy之间。所有患者的膀胱剂量范围为10至20Gy，骨表面剂量范围为39至57Gy，其他器官的剂量小于2Gy。重复给药对示踪剂的生物分布、药代动力学或器官剂量没有影响。
药代动力学分析验证了γ相机对166Ho进行全身计数是评估清除率和估计除肾脏外正常器官辐射吸收剂量的合适方法。由于166Ho的多种能量发射，定量γ相机成像困难且需要散射扣除。使用基于ROI的方法时肾脏剂量估计值比基于清除率的模型高约5倍，且两者似乎都不可靠。在未来使用166Ho-DOTMP的临床试验中，我们建议除肾脏外，对所有器官使用基于此处所述方法的剂量估计。肾脏剂量的假设需要进一步评估。
