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

Domokos Máthé, L. Balogh, András Polyák, Réka Király, T. Márián, Dariusz Pawlak, John J. Zaknun, Maroor R A Pillai, Gyozo A. Jánoki

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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 [T1/2=6.73 days, Eβmax=497 keV, Eγ=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.

Original languageEnglish
Pages (from-to)215-226
Number of pages12
JournalNuclear Medicine and Biology
Volume37
Issue number2
DOIs
Publication statusPublished - Feb 2010

Fingerprint

Radiopharmaceuticals
Pharmacokinetics
Dogs
Bone and Bones
Pain
Rabbits
Half-Life
Body Weight
Hungary
Bone Remodeling
Autoradiography
Radioisotopes
Radionuclide Imaging
Toxicology
Blood Platelets
Clinical Trials
Neoplasm Metastasis
Kidney
Therapeutics

Keywords

  • Animal studies
  • Bone seeking radiopharmaceuticals
  • In vivo biodistribution
  • Radionuclide therapy
  • Small animal imaging

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent. / Máthé, Domokos; Balogh, L.; Polyák, András; Király, Réka; Márián, T.; Pawlak, Dariusz; Zaknun, John J.; Pillai, Maroor R A; Jánoki, Gyozo A.

In: Nuclear Medicine and Biology, Vol. 37, No. 2, 02.2010, p. 215-226.

Research output: Contribution to journalArticle

Máthé, Domokos ; Balogh, L. ; Polyák, András ; Király, Réka ; Márián, T. ; Pawlak, Dariusz ; Zaknun, John J. ; Pillai, Maroor R A ; Jánoki, Gyozo A. / Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent. In: Nuclear Medicine and Biology. 2010 ; Vol. 37, No. 2. pp. 215-226.
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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 [T1/2=6.73 days, Eβmax=497 keV, Eγ=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.",
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AU - Máthé, Domokos

AU - Balogh, L.

AU - Polyák, András

AU - Király, Réka

AU - Márián, T.

AU - Pawlak, Dariusz

AU - Zaknun, John J.

AU - Pillai, Maroor R A

AU - Jánoki, Gyozo A.

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N2 - 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 [T1/2=6.73 days, Eβmax=497 keV, Eγ=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.

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