Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of ¹⁷⁷Lu-EDTMP, a potential bone pain palliation agent☆

Abstract 

Introduction

Radionuclide therapy (RNT) is an effective method for bone pain palliation in patients suffering from bone metastasis. Due to the long half-life, easy production and relatively low β− energy, ¹⁷⁷Lu [T_1/2=6.73 days, E_βmax=497 keV, E_γ=113 keV (6.4%), 208 keV (11%)]-based radiopharmaceuticals offer logistical advantage for wider use. This paper reports the results of a multispecies biodistribution and toxicity studies of ¹⁷⁷Lu-EDTMP to collect preclinical data for starting human clinical trials.

Methods

¹⁷⁷Lu-EDTMP with radiochemical purity greater than 99% was formulated by using a lyophilized kit of EDTMP (35 mg of EDTMP, 5.72 g of CaO and 14.1 mg of NaOH). Biodistribution studies were conducted in mice and rabbits. Small animal imaging was performed using NanoSPECT/CT (Mediso, Ltd., Hungary) and digital autoradiography. Gamma camera imaging was done in rabbits and dogs. Four levels of activity (9.25 through 37 MBq/kg body weight) of ¹⁷⁷Lu-EDTMP were injected in four groups of three dogs each to study the toxicological effects.

Results

¹⁷⁷Lu-EDTMP accumulated almost exclusively in the skeletal system (peak ca. 41% of the injected activity in bone with terminal elimination half-life of 2130 and 1870 h in mice and rabbits, respectively) with a peak uptake during 1–3 h. Excretion of the radiopharmaceutical was through the urinary system. Imaging studies showed that all species (mouse, rat, rabbit and dog) take up the compound in regions of remodeling bone, while kidney retention is not visible after 1 day postinjection (pi). In dogs, the highest applied activity (37 MBq/kg body weight) led to a moderate decrease in platelet concentration (mean, 160 g/L) at 1 week pi with no toxicity.

Conclusion

The protracted effective half-life of ¹⁷⁷Lu-EDTMP in bone supports that modifying the EDTMP molecule by introducing ¹⁷⁷Lu does not alter its biological behaviour as a specific bone-seeking tracer. Species-specific pharmacokinetic behavior differences were observed. Toxicity studies in dogs did not show any biological adverse effects. The studies demonstrate that ¹⁷⁷Lu-EDTMP is a promising radiopharmaceutical that can be further evaluated for establishing as a radiopharmaceutical for human use.

Keywords: Radionuclide therapy, Bone seeking radiopharmaceuticals, In vivo biodistribution, Animal studies, Small animal imaging