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Michael G Stabin

Publications and source records attributed to Michael G Stabin.

10 recordsLinked to original sources
PubMed2003

Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [(18)F]FPS.

[(18)F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [(18)F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [(18)F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [(18)F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 microg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m(2)) in these species. These data support the expectation that [(18)F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 microg FPS per injection.

Animals↗
PubMed2003

Additional radiation absorbed dose estimates for Zevalin radioimmunotherapy.

Zevalin (ibritumomab tiuxetan) radioimmunotherapy is a novel treatment for non-Hodgkin's lymphoma (NHL). The Zevalin regimen includes 5 mCi (111)In-labeled Zevalin on Day 1, followed by serial anterior and posterior planar gamma images for imaging or dosimetry. On Day 8, patients receive 0.4 mCi/kg (90)Y Zevalin for radioimmunotherapy. Both Zevalin doses are preceded by 250 mg/m(2) rituximab to clear peripheral B cells and improve biodistribution of the radiolabeled antibody. In a 143-patient, Phase III, randomized study, the Zevalin regimen produced a significantly higher overall response rate than rituximab for relapsed or refractory, low-grade, follicular, or transformed NHL (80% versus 56%, p = 0.02). Fifteen patients from the Zevalin arm of this study were randomly selected for additional radiation dosimetry. (90)Y residence times were calculated from (111)In image analysis data. MIRDOSE3.1 radiation absorbed dose estimates to normal tissues were highest for spleen, testes, and liver, with considerably lower doses reaching heart, lung, intestines, red marrow, and kidneys. Radiation absorbed doses to organs and marrow were within a safe range following administration of 0.4 mCi/kg (90)Y Zevalin.

Antibodies, Monoclonal↗
PubMed2003

Physical models and dose factors for use in internal dose assessment.

Internal dose assessment depends on the use of mathematical formulas for dose calculation and models of the human body and its organs. A simple, unified method for internal dose calculations is described, which brings together and simplifies concepts used in nuclear medicine and occupational internal dose systems previously described. Using the best current decay data and phantoms for internal dose calculations, dose factors for internal dose assessment are provided. Decay data for over 800 radionuclides from the data service at Brookhaven National Laboratory were combined with absorbed fraction data from a number of currently available mathematical whole body and organ models to provide the dose factors. This represents the first published update on nuclear medicine dose factors since MIRD Pamphlet No. 11 in 1975; in this paper, dose factors for many more nuclides are given (816 vs. 117 in MIRD 11), including some alpha emitters. New models are also employed, and dose factors for bone and marrow have been updated with recently suggested corrections. The good agreement of the new dose factors with previously published values for several of the models gives good confidence in their accuracy. This article gives an overview of the technical basis for these dose factors and some example tables of data, but the bulk of the data files will be distributed electronically. The use of an "electronic publishing" approach permits the publication of this kind of voluminous information in mainstream journals while facilitating rapid access and use without the need to purchase often expensive and bulky paper documents.

Adolescent↗
PubMed2003

Red marrow radiation dose adjustment using plasma FLT3-L cytokine levels: improved correlations between hematologic toxicity and bone marrow dose for radioimmunotherapy patients.

UNLABELLED: Calculated red marrow absorbed dose in patients receiving radioimmunotherapy (RAIT) has not been highly predictive of the dose-limiting hematologic toxicity observed in many patient populations studied. Because patients receiving the same red marrow dose often experience different grades of toxicity, other factors might help predict the different grades of toxicity observed. One such factor may be the plasma FLT3-L (FMS-related tyrosine kinase 3 ligand, hematopoiesis stimulatory cytokine) level, which has been shown to be a better indicator of recovery of progenitor cells and, thus, red marrow radiosensitivity (because during the recovery period the progenitor cells are hyperproliferative and potentially more radiosensitive) for patients treated with previous chemotherapy than peripheral blood counts. METHODS: Red marrow radiation doses were determined for 30 patients (20 male, 10 female; all without bone marrow or bone involvement; 19 had prior chemotherapy) after receiving (131)I RAIT (activity range, 2.1-8.9 GBq) for treatment of solid cancers known to produce carcinoembryonic antigen. Radiation dose estimates were calculated using 2 different methods of red marrow cumulated activity and red marrow-to-blood activity concentration ratio determinations for 2 dosimetric models: using both male and female and male-only masses and S values. Highest platelet toxicity grade at nadir (PTG), percentage platelet decrease (PPD) in counts, and platelet nadir (PN) counts were measured. FLT3-L levels (pg/mL) were determined by immunoassay before treatment; a normal FLT3-L level was assumed to be 80 pg/mL. The red marrow radiation doses (cGy) were adjusted for the patient's FLT3-L level when the patient's cytokine level exceeded the normal value. Marrow doses and FLT3-L-adjusted marrow doses were correlated with PTG, PPD, PN, and 1/PN. Administered activity, administered activity per unit body weight, and total body radiation dose were also correlated with these hematologic toxicity measures. RESULTS: All red marrow dose calculation schemes resulted in essentially the same correlations for a given hematologic toxicity measure. Poor correlations were observed between administered activity, administered activity per unit body weight, total body radiation dose, or red marrow radiation dose and PTG, PPD, PN, and 1/PN. All correlations improved greatly when the various predictors of toxicity were adjusted for the patient's FLT3-L level. The highest correlation observed was between red marrow dose or total body dose and 1/PN (r = 0.86). Using an unadjusted red marrow dose to predict toxicity >/= grade 3, there were 8 true-positive, but 13 false-positive cases with 9 true-negatives. However, using a FLT3-L-adjusted red marrow dose, there were 8 true-positives, but only 2 false-positives and 20 true-negatives. CONCLUSION: FLT3-L-adjusted red marrow radiation doses provide improved correlation with hematologic toxicity. Thus, elevated FLT3-L plasma levels before RAIT may indicate increased radiosensitivity of the bone marrow, and use of this measurement to adjust calculated red marrow or total body radiation doses may provide significantly better prediction of toxicity than radiation dose alone, leading to a patient-specific administered activity prescription that will deliver radiation doses to diseased tissues sufficient to produce an effective treatment outcome at acceptable toxicity levels.

Blood Platelets↗
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↗