Molecular radiotherapy: The NUKFIT software for calculating the time‐integrated activity coefficient

Kletting, Peter; Schimmel, S.; Kestler, Hans A.; Hänscheid, Heribert; Luster, Markus; Fernández, María Soledad; Bröer, J. H.; Noßke, D.; Laßmann, Michael; Glatting, Gerhard

doi:10.1118/1.4820367

Cited by 81 publications

(87 citation statements)

References 22 publications

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“…The dose extrapolation to humans involved the scaling of the time-integrated activity coefficients and the subsequent calculation of the absorbed doses from the animal biodistribution data using 2 different methods. Time-integrated activity coefficients were calculated using the software solution NUKFIT (28). The dose calculation was performed for a selected group of organs using OLINDA/EXM (version 1.1) (29).…”

Section: Dosimetry Calculationmentioning

confidence: 99%

⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

et al. 2015

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On the basis of the high and consistent expression of prostatespecific membrane antigen (PSMA) in metastatic prostate cancer (PC), the goal of this study was the development, preclinical evaluation, and first proof-of-concept investigation of a PSMA inhibitor for imaging and therapy (PSMA I&T) for 68 Ga-based PET and 177 Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease. Methods: PSMA I&T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of nat Ga-/ nat Lu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of 68 Ga-and 177 Lu-PSMA I&T were investigated using the same cell line, and biodistribution studies were performed in LNCaP tumor-bearing CD-1 nu/nu mice. Initial human PET imaging studies using 68 Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using 177 Lu-PSMA I&T, were performed. Results: PSMA I&T and its cold gallium and lutetium analog revealed nanomolar affinity toward PSMA. The DOTAGA (1,4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid) conjugate PSMA I&T allowed fast and high-yield labeling with 68 Ga III and 177 Lu III . Uptake of 68 Ga-/ 177 Lu-PSMA I&T in LNCaP tumor cells is highly efficient and PSMA-specific, as demonstrated by competition studies both in vitro and in vivo. Tumor targeting and tracer kinetics in vivo were fast, with the highest uptake in tumor xenografts and kidneys (both PSMA-specific). First-in-human 68 Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with 177 Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects. Conclusion: 68 Ga-PSMA I&T shows potential for high-contrast PET imaging of metastatic PC, whereas its 177 Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned.

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Section: Dosimetry Calculationmentioning

confidence: 99%

⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

et al. 2015

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“…The corrected Akaike information criterion (25) was used for model selection and parameter averaging. Models with relative standard errors greater than 50% for any estimated parameter, with elements of the correlation matrix greater than 0.8 (26) and weights less than 10% (27), were not used for model averaging.…”

Section: Pbpk Model Fitting and Selectionmentioning

confidence: 99%

Optimized Peptide Amount and Activity for ⁹⁰Y-Labeled DOTATATE Therapy

et al. 2015

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In peptide receptor radionuclide therapy with 90 Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity that can be safely administered in many patients. A higher tumor-to-kidney absorbed dose ratio might be achieved by optimizing the amount of injected peptide and activity, as recent studies have shown different degrees of receptor saturation for normal tissue and tumor. The aim of this work was to develop and implement a modeling method for treatment planning to determine the optimal combination of peptide amount and pertaining therapeutic activity for each patient. Methods: A whole-body physiologically based pharmacokinetic (PBPK) model was developed. General physiologic parameters were taken from the literature. Individual model parameters were fitted to a series (n 5 12) of planar γ-camera and serum measurements ( 111 In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, we determined the tumor, liver, spleen, and red marrow biologically effective doses (BEDs) for a maximal kidney BED (20 Gy 2.5 ) for different peptide amounts and activities. The optimal combination of peptide amount and activity for maximal tumor BED, considering the additional constraint of a red marrow BED less than 1 Gy 15 , was individually quantified. Results: The PBPK model describes the biokinetic data well considering the criteria of visual inspection, the coefficients of determination, the relative standard errors (,50%), and the correlation of the parameters (,0.8). All fitted parameters were in a physiologically reasonable range but varied considerably between patients, especially tumor perfusion (meningioma, 0.1-1 mLÁg −1 Ámin −1 , and NETs, 0.02-1 mLÁg −1 Ámin −1 ) and receptor density (meningioma, 5-34 nmolÁL −1 , and NETs, 7-35 nmolÁL −1 ). Using the proposed method, we identified the optimal amount and pertaining activity to be 76 ± 46 nmol (118 ± 71 μg) and 4.2 ± 1.8 GBq for meningioma and 87 ± 50 nmol (135 ± 78 μg) and 5.1 ± 2.8 GBq for NET patients. Conclusion: The presented work suggests that to achieve higher efficacy and safety for 90 Y-DOATATE therapy, both the administered amount of peptide and the activity should be optimized in treatment planning using the proposed method. This approach could also be adapted for therapy with other peptides.

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“…Another code called qDOSE is under development at the Royal Marsden (UK), which offers a specific version of the code aimed at dosimetry for 90 Y-RE using DVKs developed from EGSnrc environment [98]. Another recently developed user-end code called NUKDOS performs VSV dosimetry, and has been validated against OLINDA and other inhouse codes in peptide receptor radionuclide therapy (PRRT) [99].…”

Section: Dose Kernel Convolution Methodsmentioning

confidence: 99%

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

Doherty¹

2015

J Diagn Imaging Ther

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Yttrium-90 radioembolization ( 90 Y-RE) is a well-established therapy for the treatment of hepatocellular carcinoma (HCC) and also of metastatic liver deposits from other malignancies. Nuclear Medicine and Cath Lab diagnostic imaging takes a pivotal role in the success of the treatment, and in order to fully exploit the efficacy of the technique and provide reliable quantitative dosimetry that are related to clinical endpoints in the era of personalized medicine, technical challenges in imaging need to be overcome. In this paper, the extensive literature of current 90 Y-RE techniques and challenges facing it in terms of quantification and dosimetry are reviewed, with a focus on the current generation of 3D dosimetry techniques. Finally, new emerging techniques are reviewed which seek to overcome these challenges, such as highresolution imaging, novel surgical procedures and the use of other radiopharmaceuticals for therapy and pre-therapeutic planning.

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Molecular radiotherapy: The NUKFIT software for calculating the time‐integrated activity coefficient

Abstract: The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.

Cited by 81 publications

References 22 publications

⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

Optimized Peptide Amount and Activity for ⁹⁰Y-Labeled DOTATATE Therapy

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

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Molecular radiotherapy: The NUKFIT software for calculating the time‐integrated activity coefficient

Abstract: The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.

Cited by 81 publications

References 22 publications

68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

Optimized Peptide Amount and Activity for 90Y-Labeled DOTATATE Therapy

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

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⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

⁶⁸Ga- and ¹⁷⁷Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

Optimized Peptide Amount and Activity for ⁹⁰Y-Labeled DOTATATE Therapy