A “mix‐and‐use” approach for formulation of human clinical doses of ¹⁷⁷Lu‐DOTMP at hospital radiopharmacy for management of pain arising from skeletal metastases

Abstract

Use of bone-seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. Lu-DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of Lu-DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of Lu-DOTMP was developed, which involves simple mixing of approximately 3.7 GBq of Lu activity as LuCl solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO . The proposed protocol yielded Lu-DOTMP with>98% radiochemical purity, and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary clinical investigations in 5 patients showed specific skeletal accumulation with preferential localization in the osteoblastic lesion sites and almost no uptake in soft tissue or any other major nontarget organ. The developed "mix-and-use" strategy would be useful for large number of nuclear medicine centers having access to Lu activity and would thereby accelerate the clinical translation of Lu-DOTMP.

Syntheses and evaluation of 68Ga‐ and 153Sm‐labeled DOTA‐conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases

“…This gives the biodistribution data of the radiolabeled formulation for various time‐points postadministration specified above. The total uptake in blood, bone, and muscles was calculated by assuming that 7%, 10%, and 40% of the body weight are constituted by this organs/tissue, respectively . In case of 153 Sm‐ 1, one group of animals was killed at the end of 30 min, 3, 24, 48, and 96 hr postadministration.…”

Ce‐141‐labeled DOTMP: A theranostic option in management of pain due to skeletal metastases

“…All these features make 141 Ce a promising candidate for detection of metastatic skeletal lesion and palliative careof pain arising out of it using a single radiopharmaceutical formulation. A comparison of nuclear decay characteristics of 141 Ce with those of other lanthanide radionuclide being used or proposed for use in palliation of pain arising from skeletal metastases is given in Table . Moreover, 141 Ce could be produced in adequate quantity by thermal neutron activation of cerium targets in a nuclear reactor following the 140 Ce(n,γ) 141 Ce route.…”

“…Multidentate aminomethylenephosphonic acid ligands form stable complexes with β − emitting lanthanide radionuclides, and these complexes preferentially localize in the metastatic skeletal lesion sites . Among these, EDTMP is the most extensively used ligand in clinical practice in the form of [ 153 Sm]Sm‐EDTMP (Quadramet) and more recently in the form of its 177 Lu‐complex .…”

“…Lanthanide complexes of macrocyclic chelators exhibit superior kinetic rigidity compared with that of their acyclic analogues . The outcome of this is manifested in the results of the comparative animal biodistribution studies of a number of lanthanide complexes of acyclic and cyclic polyaminophosphonates, where greater kinetic lability of the complexes with acyclic chelators led to higher accumulation of activity in the liver, since dissociated radiolanthanide form colloidal hydroxides at physiological pH . In recent years, there are several reports on the formulation and evaluation of DOTMP complexes with various radiometals in animal models and in human patients.…”