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A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients

BACKGROUND: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various (68)Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compa...

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Autores principales: Siebinga, Hinke, de Wit-van der Veen, Berlinda J., Beijnen, Jos H., Dorlo, Thomas P. C., Huitema, Alwin D. R., Hendrikx, Jeroen J. M. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898489/
https://www.ncbi.nlm.nih.gov/pubmed/36735114
http://dx.doi.org/10.1186/s13550-023-00958-7
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author Siebinga, Hinke
de Wit-van der Veen, Berlinda J.
Beijnen, Jos H.
Dorlo, Thomas P. C.
Huitema, Alwin D. R.
Hendrikx, Jeroen J. M. A.
author_facet Siebinga, Hinke
de Wit-van der Veen, Berlinda J.
Beijnen, Jos H.
Dorlo, Thomas P. C.
Huitema, Alwin D. R.
Hendrikx, Jeroen J. M. A.
author_sort Siebinga, Hinke
collection PubMed
description BACKGROUND: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various (68)Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed. METHODS: A PBPK model was developed for [(68)Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect. RESULTS: Data of 39 and 59 patients receiving [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL. CONCLUSION: The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-023-00958-7.
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spelling pubmed-98984892023-02-05 A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients Siebinga, Hinke de Wit-van der Veen, Berlinda J. Beijnen, Jos H. Dorlo, Thomas P. C. Huitema, Alwin D. R. Hendrikx, Jeroen J. M. A. EJNMMI Res Original Research BACKGROUND: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various (68)Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed. METHODS: A PBPK model was developed for [(68)Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect. RESULTS: Data of 39 and 59 patients receiving [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL. CONCLUSION: The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [(68)Ga]Ga-DOTATATE and [(68)Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-023-00958-7. Springer Berlin Heidelberg 2023-02-03 /pmc/articles/PMC9898489/ /pubmed/36735114 http://dx.doi.org/10.1186/s13550-023-00958-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Research
Siebinga, Hinke
de Wit-van der Veen, Berlinda J.
Beijnen, Jos H.
Dorlo, Thomas P. C.
Huitema, Alwin D. R.
Hendrikx, Jeroen J. M. A.
A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title_full A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title_fullStr A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title_full_unstemmed A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title_short A physiologically based pharmacokinetic model for [(68)Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
title_sort physiologically based pharmacokinetic model for [(68)ga]ga-(ha-)dotatate to predict whole-body distribution and tumor sink effects in gep-net patients
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898489/
https://www.ncbi.nlm.nih.gov/pubmed/36735114
http://dx.doi.org/10.1186/s13550-023-00958-7
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