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EJNMMI Research
Published in: EJNMMI Research 1/2021

Open Access 01-12-2021 | Neuroendocrine Tumor | Original research

A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors

Authors: 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

Published in: EJNMMI Research | Issue 1/2021

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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.
Literature
1.
Bodei L, Ambrosini V, Herrmann K, Modlin I. Current concepts in68Ga-DOTATATE imaging of neuroendocrine neoplasms: Interpretation, biodistribution, dosimetry, and molecular strategies. J Nucl Med. 2017;58(11):1718–26.PubMedCrossRef
2.
Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2018;68(6):471–87.PubMedCrossRef
3.
Cives M, Strosberg J. Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep. 2017;19(2):1–9.CrossRef
4.
Pauwels E, Cleeren F, Bormans G, Deroose CM. Somatostatin receptor PET ligands - the next generation for clinical practice. Am J Nucl Med Mol Imaging. 2018;8(5):311–31.PubMedPubMedCentral
5.
Mittra ES. Neuroendocrine tumor therapy: 177 Lu-DOTATATE. Am J Roentgenol. 2018;211(2):278–85.CrossRef
6.
Kulkarni HR, Baum RP. Patient selection for personalized peptide receptor radionuclide therapy using Ga-68 somatostatin receptor PET/CT. PET Clin. 2014;9(1):83–90.PubMedCrossRef
7.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.PubMedPubMedCentralCrossRef
8.
Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of 68Ga-DOTATATE. J Nucl Med. 2013;54(6):855–60.PubMedCrossRef
9.
Sandström M, Velikyan I, Garske-Román U, Sörensen J, Eriksson B, Granberg D, et al. Comparative biodistribution and radiation dosimetry of 68Ga- DOTATOC and 68Ga-DOTATATE in patients with neuroendocrine tumors. J Nucl Med. 2013;54(10):1755–9.PubMedCrossRef
10.
Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P, et al. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol. 2016;34(6):588–97.PubMedCrossRef
11.
Kuyumcu S, Özkan ZG, Sanli Y, Yilmaz E, Mudun A, Adalet I, et al. Physiological and tumoral uptake of 68Ga-DOTATATE: standardized uptake values and challenges in interpretation. Ann Nucl Med. 2013;27(6):538–45.PubMedCrossRef
12.
Sharma R, Wang WM, Yusuf S, Evans J, Ramaswami R, Wernig F, et al. 68Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours. Radiother Oncol. 2019;141:108–15.PubMedCrossRef
13.
Bodei L, Schöder H, Baum RP, Herrmann K, Strosberg J, Caplin M, et al. Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy. Lancet Oncol. 2020;21(9):e431–43.PubMedCrossRefPubMedCentral
14.
Hardiansyah D, Maass C, Attarwala AA, Müller B, Kletting P, Mottaghy FM, et al. The role of patient-based treatment planning in peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2016;43(5):871–80.PubMedCrossRef
15.
Hardiansyah D, Attarwala AA, Kletting P, Mottaghy FM, Glatting G. Prediction of time-integrated activity coefficients in PRRT using simulated dynamic PET and a pharmacokinetic model. Phys Medica. 2017;2017(42):298–304.CrossRef
16.
Kletting P, Kull T, Maaß C, Malik N, Luster M, Beer AJ, et al. Optimized peptide amount and activity for 90Y-labeled DOTATATE therapy. J Nucl Med. 2016;57(4):503–8.PubMedCrossRef
17.
Maaß C, Sachs JP, Hardiansyah D, Mottaghy FM, Kletting P, Glatting G. Dependence of treatment planning accuracy in peptide receptor radionuclide therapy on the sampling schedule. EJNMMI Res. 2016;6(1):1–9.CrossRef
18.
Cremonesi M, Ferrari ME, Bodei L, Chiesa C, Sarnelli A, Garibaldi C, et al. Correlation of dose with toxicity and tumour response to 90Y- and 177Lu-PRRT provides the basis for optimization through individualized treatment planning. Eur J Nucl Med Mol Imaging. 2018;45(13):2426–41.PubMedPubMedCentralCrossRef
19.
20.
Dibella J, Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N, Zhuang X, et al. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation. Acta Pharm Sin B. 2016;44(July):27–9.
21.
Kuepfer L, Niederalt C, Wendl T, Schlender JF, Willmann S, Lippert J, et al. Applied concepts in PBPK modeling: how to build a PBPK/PD Model. CPT Pharmacometrics Syst Pharmacol. 2016;5(10):516–31.PubMedPubMedCentralCrossRef
22.
Niederalt C, Kuepfer L, Solodenko J, Eissing T, Siegmund HU, Block M, et al. A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. J Pharmacokinet Pharmacodyn. 2018;45(2):235–57.PubMedCrossRef
23.
Peters SA, Dolgos H. Requirements to establishing confidence in physiologically based pharmacokinetic (PBPK) models and overcoming some of the challenges to meeting them. Clin Pharmacokinet. 2019;58(11):1355–71.PubMedPubMedCentralCrossRef
24.
Kletting P, Müller B, Erentok B, Schmaljohann J, Behrendt FF, Reske SN, et al. Differences in predicted and actually absorbed doses in peptide receptor radionuclide therapy. Med Phys. 2012;39(9):5708–17.PubMedCrossRef
25.
Kletting P, Thieme A, Eberhardt N, Rinscheid A, D’Alessandria C, Allmann J, et al. Modeling and predicting tumor response in radioligand therapy. J Nucl Med. 2019;60(1):65–70.PubMedCrossRef
26.
Gospavic R, Knoll P, Mirzaei S, Popov V. Physiologically based pharmacokinetic (PBPK) model for biodistribution of radiolabeled peptides in patients with neuroendocrine tumours. Asia Ocean J Nucl Med Biol. 2016;4(2):90–907.PubMedPubMedCentral
27.
28.
Jones HM, Chen Y, Gibson C, Heimbach T, Parrott N, Peters SA, et al. Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective. Clin Pharmacol Ther. 2015;97(3):247–62.PubMedCrossRef
29.
FDA, CDER. Lutathera® lutetium dotatate LU-177 - Label data. 2018;1–14.
30.
Pilari S, Gaub T, Block M, Görlitz L. Development of physiologically based organ models to evaluate the pharmacokinetics of drugs in the testes and the thyroid gland. CPT Pharmacometrics Syst Pharmacol. 2017;6(8):532–42.PubMedPubMedCentralCrossRef
31.
Bodei L, Paganelli G, Mariani G. Receptor radionuclide therapy of tumors: A road from basic research to clinical applications. J Nucl Med. 2006;47(3):375–7.PubMed
32.
Hofland LJ, Lamberts SWJ. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24(1):28–47.PubMedCrossRef
33.
34.
Kaemmerer D, Peter L, Lupp A, Schulz S, Sänger J, Prasad V, et al. Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2011;38(9):1659–68.PubMedCrossRef
35.
Reubi JC. Peptide receptor expression in GEP-NET. Virchows Arch. 2007;451(SUPPL. 1):47–50.CrossRef
36.
Fani M, Nicolas GP, Wild D. Somatostatin receptor antagonists for imaging and therapy. J Nucl Med. 2017;58:61S-66S.PubMedCrossRef
37.
Waser B, Tamma ML, Cescato R, Maecke HR, Reubi JC. Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. J Nucl Med. 2009;50(6):936–41.PubMedCrossRef
38.
Marino S, Hogue IB, Ray CJ, Kirschner DE. A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol. 2008;254(1):178–96.PubMedPubMedCentralCrossRef
39.
40.
41.
Schottelius M, Šimeček J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ. Twins in spirit—episode I: comparative preclinical evaluation of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. EJNMMI Res. 2015;5(1):1–10.CrossRef
42.
Xia Y, Zeng C, Zhao Y, Zhang X, Li Z, Chen Y. Comparative evaluation of 68Ga-labelled TATEs: the impact of chelators on imaging. EJNMMI Res. 2020;10(1):1–11.CrossRef
43.
Reubi JC, Schär J, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1–SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82.PubMedCrossRef
44.
Ferl GZ, Dumont RA, Hildebrandt IJ, Armijo A, Haubner R, Reischl G, et al. Derivation of a compartmental model for quantifying 64Cu-DOTA-RGD kinetics in tumor-bearing mice. J Nucl Med. 2012;50(2):250–8.CrossRef
45.
Kao YJ, Ghosh M, Schonbrunn A. Ligand-dependent mechanisms of sst2A receptor trafficking: Role of site-specific phosphorylation and receptor activation in the actions of biased somatostatin agonists. Mol Endocrinol. 2011;25(6):1040–54.PubMedPubMedCentralCrossRef
46.
47.
Jiménez-Franco LD, Glatting G, Prasad V, Weber WA, Beer AJ, Kletting P. Effect of tumor perfusion and receptor density on tumor control probability in 177Lu-DOTATATE therapy: an in silico analysis for standard and optimized treatment. J Nucl Med. 2021;62(1):92–8.PubMedCrossRef
48.
Chakravarty R, Chakraborty S, Ram R, Vatsa R, Bhusari P, Shukla J, et al. Detailed evaluation of different 68Ge/68Ga generators: an attempt toward achieving efficient 68Ga radiopharmacy. J Label Compd Radiopharm. 2016;59(3):87–94.CrossRef
49.
Velikyan I, Sundin A, Eriksson B, Lundqvist H, Sörensen J, Bergström M, et al. In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours - impact of peptide mass. Nucl Med Biol. 2010;37(3):265–75.PubMedCrossRef
50.
Sabet A, Nagarajah J, Dogan AS, Biersack HJ, Sabet A, Guhlke S, et al. Does PRRT with standard activities of 177Luoctreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: Insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors. EJNMMI Res. 2013;3(1):1–6.CrossRef
51.
Boy C, Heusner TA, Poeppel TD, Redmann-Bischofs A, Unger N, Jentzen W, et al. 68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUV max. Eur J Nucl Med Mol Imaging. 2011;38(7):1224–36.PubMedCrossRef
52.
Shastry M, Kayani I, Wild D, Caplin M, Visvikis D, Gacinovic S, et al. Distribution pattern of 68Ga-DOTATATE in disease-free patients. Nucl Med Commun. 2010;31(12):1025–32.PubMedCrossRef
53.
Velikyan I, Sundin A, Sörensen J, Lubberink M, Sandström M, Garske-Román U, et al. Quantitative and qualitative intrapatient comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: Net uptake rate for accurate quantification. J Nucl Med. 2014;55(2):204–10.PubMedCrossRef
54.
Hennrich U, Kopka K. Lutathera®: the first FDA-and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals. 2019;12(3):114.PubMedCentralCrossRef
55.
Begum NJ, Thieme A, Eberhardt N, Tauber R, D’Alessandria C, Beer AJ, et al. The effect of total tumor volume on the biologically effective dose to tumor and kidneys for 177 Lu-Labeled PSMA peptides. J Nucl Med. 2018;59(6):929–33.PubMedCrossRef
Metadata
Title
A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors
Authors
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
Publication date
01-12-2021
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2021
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-021-00821-7

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