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

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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.

Introduction

Treatment of unresectable, often incurable multiple skeletal cancer metastases is one of the major challenges of oncological practice. Most commonly used palliative treatment modalities are external beam radiation therapy, morphine-derived analgesics and bisphosphonates [1], [2], [3], [4]. However, in a significant number of patients radiotherapy is not an option due to the location or multiplicity of tumors, and the effect of analgesia is insufficient. Radiation delivered directly and in a targeted manner to the tumor cells and their microenvironment is a possible way to overcome these obstacles. In this context, intravenous radionuclide therapy (RNT) aimed at pain palliation of incurable multiple skeletal metastases with bone-seeking agents is a well-established but yet underexploited modality [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. According to the clinical trials, RNT improves the quality of life in a higher percentage of patients than applying conventional treatment methods, also in cases where morphine derivatives or bisphosphonates give less satisfactory effect [16], [17], [18], [19]. Several isotopes have been applied in the above-referenced studies. Currently, the most widely used and registered preparations make use of 153Sm (153Sm-EDTMP) and 89Sr (89Sr-chloride). Other isotopes coupled to bone-seeking molecules in clinical use include 186Re [9], [20], [21], [22] and 188Re [22], [23], [24].

Systemic application of ethylene diamine-N,N,N′,N′-tetrakis(methylene phosphonic acid) (EDTMP) labeled with 153Sm as a bone-seeking agent has been studied and applied in clinical practice in a large number of patients for more than two decades. The clinical efficacy of this radiopharmaceutical is well demonstrated [4], [6], [15], [16], [17], [18], [19], [20]. However, the short half-life of 153Sm (T1/2 47 h) has been the major impediment, making its transportation difficult and thereby limiting its wider use.

Lutetium-177 [T1/2=6.73 days, Eβmax=497 keV, Eγ=113 keV (6.4%), 208 keV (11%)] has several advantages to be explored as a therapeutic radionuclide for bone pain palliation [25]. First, its lower beta-particle energy and relatively long physical half-life allow the deposition of an adequate tumor irradiation dose with a constant dose rate [26], [27]. A model calculation published suggests that 177Lu is the optimal radionuclide for full beta-particle energy deposition in small tumor volumes [26]. The high cross section of the target radionuclide [176Lu(n,γ)177Lu σ=2100 barns] allows large-scale production of 177Lu even while using medium flux research reactors. The relatively long half-life (6.73 days) of 177Lu allows easy transportation of the isotope thereby improving the accessibility of RNT to more patients and in countries which have no reactor accessibility. The low-energy, low-yield [Eγ=113 keV (6.4%), 208 keV (11%)] gamma photon emissions of 177Lu allow scintigraphic detection of the tracer in vivo to estimate the dose in individual patients. Considering the above advantages of 177Lu, the International Atomic Energy Agency (IAEA) initiated a project towards the introduction of 177Lu-based radiopharmaceuticals for bone pain palliation.

A variety of cyclic and acyclic polyamino-polyphosphonates were evaluated as potential radiopharmaceuticals [28], [29], [30], [31], [32]. In comparative evaluation studies of the 177Lu complexes of different acyclic and cyclic phosphonate ligands, DOTMP and EDTMP were found to give superior results over other phosphonates [30], [31]. As already sufficient data are available on the biological tolerance of the ligand EDTMP as well as the radiopharmaceutical 153Sm-EDTMP, EDTMP was selected as the carrier ligand for the IAEA-sponsored studies. It was felt that replacing the radionuclide 153Sm with 177Lu in the EDTMP complex will pose minimal additional chemical or radiological toxicity issues. Consequently, a detailed study on the biodistribution and imaging of 177Lu-EDTMP in rats, rabbits and beagle dogs was conducted [33] which showed highly promising results. In the present studies, we aimed at obtaining detailed biodistribution and pharmacokinetic parameters of 177Lu-EDTMP in several species to study the pharmacological effects. Mouse, rats, rabbits and dogs were used for the biodistribution and imaging studies. Data from the biodistribution studies were used to calculate pharmacokinetic parameters based on a noncompartmental model. Skeletal retention of the agent and its potential radiotoxic effects were studied by injecting 177Lu-EDTMP activity at different levels in beagle dogs.

Section snippets

Radiopharmaceutical preparation and quality control

Lutetium-177 as chloride in 0.5N HCl was obtained from AEA GmbH (Germany) or POLATOM Ltd. (Poland). The specific activity of 177Lu used in these studies was >5 Ci/mg (185 GBq/mg). Lyophilized kits of the radiopharmaceutical used in the studies were produced at Radioisotope Centre, POLATOM (Poland), or at Medi-Radiopharma, Ltd. (Hungary). The kit consisted of 35 mg EDTMP (0.077 mM), 5.72 mg CaO (0.102 mM), 14.1 mg NaOH (0.35 mM). The radiopharmaceutical is formulated by the addition of 1 ml of

Biodistribution studies in mice

The results of the biodistribution studies in mice at different time points studied are summarized in Table 1. Accumulation of activity in the bone is fast and peaks at 2 h pi. (40.82±3.98 %IA in bone). Activity accumulation was primarily observed in the bones with fast excretion via the urinary system. No organs other than the bone showed retention of activity in significant amount at any time point. The pharmacokinetic parameters calculated from the biodistribution data are presented in Table

Discussion

The composition of the freeze-dried EDTMP kits used in the present studies was matched to the registered product of 153Sm-EDTMP. Detailed quality control of the kits including sterility, apyrogenicity and long-term stability was established. The radiochemical purity as well as the stability of the complex over a period of time was studied. The 177Lu-EDTMP complexation yield was greater than 99% to start with and there was no significant reduction in the radiochemical purity over several days of

Conclusion

We examined the biodistribution, pharmacokinetic, biochemical and hematologic parameters of 177Lu-EDTMP in different species in order to collect data to support a human clinical trial. The biodistribution, autoradiography and imaging studies of 177Lu-EDTMP clearly demonstrate that the tracer is taken up almost exclusively by the skeletal system, with minimal activity accumulation in any other organ. Multidose studies up to 37 MBq/kg bw in dogs did not result in any adverse effects as seen from

Acknowledgments

The protocol for the reported studies was finalized during a consultants' meeting organized by IAEA during 2006 and the authors are thankful to Dr. W.A. Volkert, Dr. Renata Mikolajczak and Dr. Meera Venkatesh who participated in the consultants' meeting and gave valuable suggestions. Károly Haller and Norbert Fésüs are acknowledged for their kind help in performing the experiments. Radioisotope Centre POLATOM and Medi-Radiopharma Ltd. are gratefully acknowledged for their support in providing

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    Part of this work was conducted under an International Atomic Energy Agency (IAEA) Coordinated Research Project and a European Commission FP6 grant to the European Molecular Imaging Laboratories (LSH-CT 2004-503569).

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