Radiopharmacokinetic modelling and radiation dose assessment of 223Ra used for treatment of metastatic castration-resistant prostate cancer

Abstract Purpose Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study. Methods The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, $$ \overset{\sim }{a}\left({r}_S,{T}_D\right), $$ a ~ r S T D , in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned $$ \overset{\sim }{a}\left({r}_S,{T}_D\right) $$ a ~ r S T D values. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

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Radiopharmacokinetic Modelling and Radiation Dose Assessment of 223ra Used for Treatment of Metastatic Castration Resistant Prostate Cancer

10.21203/rs.3.rs-41574/v1 ◽

2020 ◽

Author(s):

Vera Höllriegl ◽

Nina Petoussi-Henss ◽

Juan Camilo Ocampo Ramos ◽

Wei Bo Li

Keyword(s):

Prostate Cancer ◽

Dose Assessment ◽

Radiological Protection ◽

Bolus Administration ◽

Time Activity ◽

Biokinetic Model ◽

Castration Resistant ◽

Red Marrow ◽

Dose Coefficients ◽

Modelling Study

Abstract Purpose Ra-223-Dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny and dosimetric framework developed by the International Commission on Radiological Protection (ICRP) and to show their radiopharmacokinetic behaviour. Organ absorbed and equivalent doses after intravenous injection of 223Ra were estimated and compared to clinical data and other modelling study. Methods The most recent ICRP systemic biokinetic model of 223Ra and its progeny as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics was assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned values to estimate the organ absorbed and equivalent doses. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinic trials. The highest absorbed dose coefficients were found for bone endosteum, liver, and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values from clinical studies and of a previous compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

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Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05022-3 ◽

2020 ◽

Author(s):

Vasko Kramer ◽

René Fernández ◽

Wencke Lehnert ◽

Luis David Jiménez-Franco ◽

Cristian Soza-Ried ◽

...

Keyword(s):

Prostate Cancer ◽

Whole Body ◽

Published Data ◽

Albumin Binding ◽

Castration Resistant Prostate Cancer ◽

Effective Treatment Option ◽

Binding Properties ◽

Castration Resistant ◽

Red Marrow ◽

Therapeutic Outcomes

Abstract Introduction PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. Methods Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. Results [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. Conclusion Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

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Dosimetry of 177Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer: A sub-study of the VISION trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps265 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS265-TPS265 ◽

Cited By ~ 1

Author(s):

Jens Kurth ◽

Ken Herrmann ◽

Matthias Eiber ◽

Kambiz Rahbar ◽

Martin Heuschkel ◽

...

Keyword(s):

Prostate Cancer ◽

Single Photon ◽

Photon Emission ◽

Calibration Procedure ◽

Whole Body ◽

Treatment Modalities ◽

Emission Computed Tomography ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Absorbed Doses

TPS265 Background: Prostate-specific membrane antigen-617 labelled with lutetium-177 (177Lu-PSMA-617) is a promising treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with taxane chemotherapy and a novel androgen axis inhibitor. The radiotherapeutic molecule has high PSMA binding affinity, prolonged tumor retention with a rapid kidney clearance, and high tumor-to-background ratio, delivering therapeutically relevant doses of radiation to prostate cancer lesions. A randomized, prospective phase 3 trial to assess the efficacy of 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC is ongoing (VISION trial, NCT03511664). However, as with other targeted radionuclide treatment modalities, there may be a risk of radiotoxicity to normal organs. Therefore, estimation of absorbed doses in these organs in a representative manner within the framework of such a study is essential. Methods: As a substudy of the VISION trial, extensive intratherapeutic dosimetry will be performed in a group of 30 patients at four participating German sites. Patients will undergo planar whole-body scintigraphy scans and single-photon emission computed tomography/computerized tomography (SPECT/CT) scans of the upper and lower abdomen at approximately 2, 24, and 48 hours, and 7 days after administration, along with blood sampling and urine collection. SPECT/CT data will be quantitatively reconstructed and a standardized calibration procedure of the imaging and measurement equipment used (SPECT/CT, dose calibrator, well counter) will be performed at all sites according to European Association of Nuclear Medicine (EANM) and Medical International Radiation Dose (MIRD) guidelines [1]. Organ masses will be measured for each patient using CT imaging, if accessible. Absorbed doses for kidneys, liver, spleen, salivary and lacrimal glands, and bone marrow, as well as prostate cancer lesions, will be calculated for each patient following international guidelines [2,3]. References: [1] Ljungberg M et al. J Nucl Med 2016;57:151–62. [2] Siegel JA et al. J Nucl Med 1999;40:37S–61S. [3] Hindorf C et al. Eur J Nucl Med Mol Imaging 2010;37:1238–50. Clinical trial information: NCT03511664.

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177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: Biokinetics, Dosimetry, and Evaluation in Patients with Advanced Prostate Cancer

Contrast Media & Molecular Imaging ◽

10.1155/2018/5247153 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Clara Santos-Cuevas ◽

Guillermina Ferro-Flores ◽

Francisco O. García-Pérez ◽

Nallely Jiménez-Mancilla ◽

Gerardo Ramírez-Nava ◽

...

Keyword(s):

Prostate Cancer ◽

Healthy Subjects ◽

Slow Component ◽

Optimal Number ◽

Molecular Probe ◽

Whole Body ◽

Body Images ◽

Time Activity ◽

Biokinetic Model ◽

Before And After

SPECT/CT images in patients have demonstrated the ability of [99mTc]Tc-EDDA/HYNIC-Lys(Nal)-Urea-Glu ([99mTc]Tc-iPSMA) to detect tumors and metastases of prostate cancer. Considering that theranostics combines the potential of therapeutic and diagnostic radionuclides in the same molecular probe, the aim of this research was to estimate the biokinetics and dosimetry of 177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu (177Lu-iPSMA) in healthy subjects and analyze the response in patients receiving 177Lu-iPSMA therapeutic doses. 177Lu-iPSMA was obtained from lyophilized formulations with radiochemical purities >98%. Whole-body images from five healthy subjects were acquired at 20 min, 6, 24, 48, and 120 h after 177Lu-iPSMA administration (185 MBq). The image sequence was used to extrapolate the 177Lu-iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. Ten patients (median age: 68 y; range 58–86 y) received from 1 to 4 cycles of 177Lu-iPSMA (3.7 or 7.4 GBq) every 8–10 weeks. Response was evaluated using the 68Ga-PSMA-ligand-PET/CT or 99mTc-iPSMA-SPECT/CT diagnostic images and serum PSA levels before and after 177Lu-iPSMA treatment. The blood activity showed a half-life value of 1.1 h for the fast component (T1/2α = ln2/0.614), 9.2 h for the first slow component (T1/2β = ln2/0.075), and 79.6 h for the second slow component (T1/2γ = ln2/0.008). The average absorbed doses were 0.23, 0.28, 0.88, and 1.17 Gy/GBq for the spleen, liver, kidney, and salivary glands. A total of 18 cycles were performed in 10 patients. A PSA decrease and some reduction of the radiotracer uptake (SUV) in tumor lesions occurred in 60% and 70% of the patients, respectively. 177Lu-iPSMA obtained from kit formulations showed high tumor uptake with good response rates in patients. The results obtained in this study warrant further clinical studies to establish the optimal number of treatment cycles and for evaluating the effect of this therapeutic agent on survival of patients.

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