Biomedical subjects

Michael G Stabin

Publications and source records attributed to Michael G Stabin.

24 records · Page 2Linked to original sources

PubMed2003

Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice.

UNLABELLED: B lymphocyte stimulator (BLyS) protein is a member of the tumor necrosis factor (TNF) superfamily of cytokines that binds to B lineage cells, but not T cells, monocytes, natural killer cells, or granulocytes. BLyS protein binding to B cells is restricted to immunoglobulin-positive cells and is not evident on pro- or pre-B cell populations. This unique binding profile suggests that a radiolabeled form of BLyS protein may be a useful treatment for B cell neoplasias such as B cell lymphoma and multiple myeloma. Here, we report the biodistribution of radiolabeled recombinant human BLyS after intravenous injection into normal mice and mice bearing BCL1 tumor in the spleen or J558 tumor in the subcutaneous space. We also report the use of these data to estimate human dosimetry. METHODS: (125)I-Labeled BLyS protein (50 micro g/kg, 0.185-0.37 MBq per mouse) was injected intravenously into BALB/c mice, and biodistribution was measured by direct counting of radioactivity in dissected tissues and by quantitative whole-body autoradiography (QWBA). RESULTS: The half-life of radiolabeled BLyS protein in blood was approximately 2.7 h in both normal and tumor-bearing mice. The spleen showed the highest uptake of BLyS protein in both normal and tumor-bearing mice, with a maximum concentration (C(max)) of 35-45 percentage injected dose per gram (%ID/g) occurring between 1 and 3 h after injection. In lymph nodes, C(max) was approximately 20 %ID/g in normal and J558 tumor-bearing mice and 8-15 %ID/g in BCL1 tumor-bearing mice. Limited biodistribution data from the J558 tumors showed a C(max) of approximately 15 %ID/g. By contrast, C(max) was only approximately 5 %ID/g for both kidney and liver. QWBA confirmed high radioactivity in spleen, lymph nodes, and stomach contents and low radioactivity in kidney and liver. After 24 h, spleen and lymph nodes were still positive in QWBA images, whereas liver and kidney no longer had observable levels. CONCLUSION: Radiolabeled BLyS showed specific and rapid targeting to lymphoid tissues and B cell tumors in mice. Unlike monoclonal antibodies, which have long plasma half-lives and considerable liver uptake, BLyS has distinct pharmacokinetic and biodistribution properties that may offer advantages compared with antibody-based radioimmunotherapy.

Animals↗

PubMed2003

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials.

UNLABELLED: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data. METHODS: Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow. RESULTS: Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC. CONCLUSION: Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.

Adult↗

PubMed2002

Sensitivity of model-based calculations of red marrow dosimetry to changes in patient-specific parameters.

We have investigated several of the key model parameters and assumptions involved in the calculation of red marrow absorbed dose in order to better understand the sensitivity of the predicted results to changes in these model features and the subsequent effect on correlations of the red marrow absorbed dose values with observed hematologic toxicity. Red marrow dose calculations based on measured blood activity concentrations (to determine red marrow cumulated activity) and measured total body cumulated activity have a mass-independent and mass-dependent term. Adjustments for patient mass should be made in these calculations when patients' lean body masses are more than 10% different from that in the assumed standard models. The blood-based red marrow dose methodology has the potential to provide a reasonable estimate of red marrow dose as long as there is no specific uptake in red marrow or bone due to the presence of free radionuclide, disease, or retention of activity due to metabolism by the reticuloendothelial system. If these additional sources of red marrow dose are present, the blood-based methodology will significantly underestimate red marrow dose. For radiometals, such as in (90)Y-labeled antibodies, bone or red marrow uptake of free yttrium or catabolized (90)Y products may have a significant impact on the calculated dose, assuming fairly low amounts of free (90)Y or marrow activity uptake (5-10%), even in the absence of disease in red marrow and/or bone. This is also true for (131)I-labeled antibodies, although to a lesser extent due to typically reduced activity retention in the bone marrow in the absence of disease and lack of bone uptake of free radionuclide. Radiation dose calculations for the red marrow must be made as carefully as possible, taking into account all possible sources of radiation dose, and considering all sources of uncertainties, in order to give the best possible correlations of radiation dose with observed toxicity.

Bone Diseases↗

PubMed2002

Decay data for internal and external dose assessment.

Decay data for use in internal and external dose assessment are presented. Decay data for more than 800 radionuclides were taken from the Brookhaven National Laboratory database and formatted for use in internal or external dose assessment (giving nuclide half-life, decay types, energies, and abundances). Data are provided in both a Microsoft Word document and Excel spreadsheet, both of which are too large for publication in a journal. The technical basis for the data are given here, and the data are available via electronic transfer from a web site. These recently extracted data provide an update on previously published decay data values in a form readily accessible by many users worldwide.

Databases as Topic↗

PubMed2002

The importance of patient-specific radiation dose calculations for the administration of radionuclides in therapy.

This paper advocates patient-specific approaches to radiation dose calculations for radionuclides used in therapy and outlines strategies for implementing such approaches. The use of a simple approaches to radionuclide therapy, e.g. a single amount of activity for all patients or the same amount of activity administered per unit body weight do not permit the optimization of individual patient therapy. While limitations in current models and logistic problems prevent dose calculations of the quality currently enjoyed with external radiation therapy approaches, improvements can be made, and models are constantly evolving. Specific suggestions regarding the extension of current models, and of the use of new models which use image data from individual patients, are discussed in the context of allowing radiotherapy with internal emitters to employ the kind of patient-specific approaches that are used in other therapeutic modalities, which are clearly in the patients' best interests.

Bone Marrow↗

PubMedDate not supplied

Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer, [18F]SFE.

[(18)F]1-(2-Fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]SFE) is a novel, selective, high-affinity sigma-1 receptor radioligand that has been preclinically well characterized in rodents. To support an investigational new drug (IND) application for the first evaluation of [(18)F]SFE in humans, single-organ and whole-body radiation adsorbed doses associated with [(18)F]SFE injection were estimated from rat distribution data. In addition, single- and multiple-dose toxicity studies were conducted in rabbits and in dogs. Multiple-dose toxicity studies in rabbits and single-dose toxicity studies in beagles suggest at least a 100-fold safety margin for humans studies at a mass dose limit of 4.0 mug per intravenous injection, based on the combined no observable adverse effect levels (NOAEL, mg/m(2)) measured in these species. Radiation dosimetry estimates obtained from rat biodistribution analyses of [(18)F]SFE suggest that most tissues would receive about 0.010-0.020 mGy/MBq, while the adrenal glands, brain, bone, liver, lungs, and spleen would receive slightly higher doses (0.024-0.044 mGy/MBq). The adrenal glands were identified as the critical organ, because they received the highest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]SFE is well below the FDA-defined limits for yearly cumulative and per-study exposures to research participants. These combined results support the expectation that [(18)F]SFE will be safe for use in human positron emission tomography (PET) imaging studies with the administration of 5 mCi and a mass dose equal to or less than 4.0 mug SFE per injection.

Animals↗