A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors
Abstract Background Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokin...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
SpringerOpen
2021-08-01
|
| Series: | EJNMMI Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13550-021-00821-7 |
| _version_ | 1818722020681056256 |
|---|---|
| author | H. Siebinga B. J. de Wit-van der Veen J. H. Beijnen M. P. M. Stokkel T. P. C. Dorlo A. D. R. Huitema J. J. M. A. Hendrikx |
| author_facet | H. Siebinga B. J. de Wit-van der Veen J. H. Beijnen M. P. M. Stokkel T. P. C. Dorlo A. D. R. Huitema J. J. M. A. Hendrikx |
| author_sort | H. Siebinga |
| collection | DOAJ |
| description | Abstract Background Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). Methods Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30–60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. Results 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05–16.9 µg) labeled with 92.7 MBq (range 43.4–129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. Conclusions To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts. |
| first_indexed | 2024-12-17T20:47:59Z |
| format | Article |
| id | doaj.art-fe2a704d85784b949bb268588895a863 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-17T20:47:59Z |
| publishDate | 2021-08-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-fe2a704d85784b949bb268588895a8632022-12-21T21:33:07ZengSpringerOpenEJNMMI Research2191-219X2021-08-0111111210.1186/s13550-021-00821-7A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumorsH. Siebinga0B. J. de Wit-van der Veen1J. H. Beijnen2M. P. M. Stokkel3T. P. C. Dorlo4A. D. R. Huitema5J. J. M. A. Hendrikx6Department of Pharmacy and Pharmacology, The Netherlands Cancer InstituteDepartment of Nuclear Medicine, The Netherlands Cancer InstituteDepartment of Pharmacy and Pharmacology, The Netherlands Cancer InstituteDepartment of Nuclear Medicine, The Netherlands Cancer InstituteDepartment of Pharmacy and Pharmacology, The Netherlands Cancer InstituteDepartment of Pharmacy and Pharmacology, The Netherlands Cancer InstituteDepartment of Pharmacy and Pharmacology, The Netherlands Cancer InstituteAbstract Background Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). Methods Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30–60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. Results 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05–16.9 µg) labeled with 92.7 MBq (range 43.4–129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. Conclusions To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.https://doi.org/10.1186/s13550-021-00821-7PBPK modelingWhole-body distribution68Ga-DOTATATEPRRTPeptide amountSSTR2 |
| spellingShingle | H. Siebinga B. J. de Wit-van der Veen J. H. Beijnen M. P. M. Stokkel T. P. C. Dorlo A. D. R. Huitema J. J. M. A. Hendrikx A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors EJNMMI Research PBPK modeling Whole-body distribution 68Ga-DOTATATE PRRT Peptide amount SSTR2 |
| title | A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors |
| title_full | A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors |
| title_fullStr | A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors |
| title_full_unstemmed | A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors |
| title_short | A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors |
| title_sort | physiologically based pharmacokinetic pbpk model to describe organ distribution of 68ga dotatate in patients without neuroendocrine tumors |
| topic | PBPK modeling Whole-body distribution 68Ga-DOTATATE PRRT Peptide amount SSTR2 |
| url | https://doi.org/10.1186/s13550-021-00821-7 |
| work_keys_str_mv | AT hsiebinga aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT bjdewitvanderveen aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT jhbeijnen aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT mpmstokkel aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT tpcdorlo aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT adrhuitema aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT jjmahendrikx aphysiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT hsiebinga physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT bjdewitvanderveen physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT jhbeijnen physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT mpmstokkel physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT tpcdorlo physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT adrhuitema physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors AT jjmahendrikx physiologicallybasedpharmacokineticpbpkmodeltodescribeorgandistributionof68gadotatateinpatientswithoutneuroendocrinetumors |