Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine – a review

Purpose The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE. NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals. Methods A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting. Results Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago. Conclusion It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained

Improving radioimmunotargeting of tumors : the impact of extracorporeal immunoadsorption and preload in rats

In radioimmunotherapy of tumors, uptake of the monoclonal antibody (MAb) used is often too low in relation to its uptake in normal tissues. The purpose of these studies was to improve experimental tumor radioimmunotargeting with (a) extracorporeal immunoadsorption (ECIA), where excess of radiolabeled MAbs circulating in blood is removed, (b) or by preload with unlabeled MAb prior to injection of radiolabeled MAb, (c) or by a combination of these. ECIA based on the avidin-biotin concept enables direct adsorption of radiolabeled and biotinylated MAb from blood and increases the tumor-to-normal tissue (T/N) uptake ratio by reducing background radioactivity in radiosensitive organs. 267 rats (athymic or Brown Norwegian) grafted with human adenocarcinoma or rat colon adenocarcinoma tumors intramuscularly, and beneath the kidney or liver capsule were included in the studies. Of these rats, 82 were subjected to ECIA. Two radioiodinated and biotinylated MAbs, murine L6 or chimeric BR96, were used and evaluated. (I) Using 50 µg dosage of L6, ECIA reduced whole body and plasma activity as well as improved the detectability of subrenal capsule tumors. T/N uptake ratios were increased on average 3 times. (II) The efficacy of ECIA in removing different injected amounts of L6 from plasma was similar. The highest T/N ratios persisting 24h after start of the ECIA were obtained by using 10 µg of 125I-L6-biotin. (III) The efficacy of preload in enhancing tumor uptake and simultaneously decreasing uptake in normal tissues was obtained with 250µg of 125I-L6 preceded by a preload of 50µg unlabeled L6 only. (IV) The effects on radioimmunotargeting of preload and ECIA in combination were synergistic and improved T/N uptake ratios up to 17 times. (V) As compared with ECIA, a new method of whole blood immunoadsorption (WBIA) was technically easier to perform, safer and more reliable, but of approx. comparable efficiency. (VI) WBIA was even applicable on the internalizing and highly tumor selective 125I-BR96-biotin MAb, resulting in manifestly improved T/N ratios

Radio-immunotherapy dosimetry with special emphasis on SPECT quantification and extracorporeal immuno-adsorption

Results from therapeutic trials with radiolabelled monoclonal antibodies are difficult to compare, because of lack of accurate macroscopic and microscopic dosimetry for both tumours and normal tissues. Requirements for such a dosimetry are covered in the paper. Accurate in vivo dosimetric measurement techniques for verification of calculated absorbed doses are also needed to verify treatment planning. In the review, important topics related to dosimetry in therapeutic trials in RIT are covered, such as, absorbed-dose calculations and activity-quantification techniques for planar imaging and SPECT. The latter is particularly discussed, including a summary of different correction techniques. Absorbed-dose calculations and treatment-planning techniques are also discussed. Possible ways of enhancing the therapeutic ratio are reviewed, especially the novel technique with extracorporeal immuno-adsorption. The review could form the basis of the development of future treatment-planning protocols and for dosimetry calculations in radio-immunotherapy, considering some of the most important parameters for approaching an accurate in vivo dosimetry

High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma.

We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma

Application of extracorporeal immunoadsorption to reduce circulating blood radioactivity after intraperitoneal administration of indium-111-HMFG1-biotin.

BACKGROUND: Extracorporeal immunoadsorption (ECAT) is a method of reducing activity in radiosensitive organs by removing excess monoclonal antibodies (MAbs) from the blood. Previously, the authors experimentally evaluated ECAT based on the avidin-biotin concept after intravenous administration of radioimmunoconjugates. The aim of the current study was to determine whether ECAT could be used to reduce activity after intraperitoneal (i.p.) administration of indium-111((111)In)-HMFG1-biotin in rats, and to compare the pharmacokinetics of (111)In-HMFG1 with or without attached biotin after i.p. injection. METHODS: HMFG1, a murine immunoglobulin G(1) MAb that recognizes an epitope on the polymorphic epithelial mucin (PEM) antigen, was labeled with (111)In and then biotinylated. ECAT was explored from unseparated blood using an avidin-agarose adsorption column. Thirty rats were used as controls and 13 underwent ECAT. The whole-body (WB), blood, and organ activity were monitored. RESULTS: The binding capacity of (111)In-HMFG1-biotin to avidin was high. Biotinylation did not enhance the excretion of HMFG1. When ECAT was employed, the WB and blood radioactivity were reduced by 35-40% (P < 0.05) and 75--86% (P < 0.01), respectively. After the completion of ECAT, the activity uptake in organs was significantly decreased. CONCLUSIONS: ECAT was successfully applied after i.p. injection of the (111)In-HMFG-biotin MAb to reduce the radioactivity in the WB, blood, and radiosensitive organs. Due to redistribution of the radiolabeled MAbs during and after the completion of ECAT, the adsorption may have been prolonged or repeated. Biotinylation did not significantly change the biodistribution of the (111)In-HMFG1 in rats after intraperitoneal injection