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Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera®) Case

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Lu-177 DOTATATE (Lutathera®) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment. The aim of this work was to study the pharmacokinetics of Lu-177 DOTATATE by a population modeling approach, based on single-photon emission computed tomography (SPECT)/computed tomography (CT) images used as surrogate of plasma concentrations to study the interindividual variability and finally optimize an individual dosage.

Methods

From a retrospective study, SPECT/CT images were acquired at 4 h, 24 h, 72 h, and 192 h postadministration. From these images, volumic activities were calculated in blood and bone marrow. An individual non-compartmental pharmacokinetic analysis was performed, and the mean pharmacokinetic parameters of each tissue were compared together and with reference data. Blood volumic activities were then used to perform a population pharmacokinetic analysis (NONMEM).

Results

The pharmacokinetic parameters (non-compartmental analysis) obtained from blood (clearance [CL] = 2.65 L/h, volume of distribution at steady state [Vss] = 309 L, elimination half-life [t1/2] = 86.3 h) and bone marrow (CL =1.68 L/h, Vss = 233 L, t1/2 = 98.8 h) were statistically different from each other and from reference values (CL = 4.50 L/h, Vss = 460 L, t1/2 = 71.0 h) published in the literature. SPECT/CT blood images were used as a surrogate of plasma concentrations to develop a population pharmacokinetic model. Weight was identified as covariate on volume of the central compartment, reducing the interindividual variability of all population pharmacokinetic parameters.

Conclusion

This study is a proof of concept that obtaining pharmacokinetic parameters with image-based blood concentration is possible. Obtaining observed concentrations from SPECT/CT images, without the need for blood sampling, is a real advantage for the patient and the drug monitoring. Pharmacokinetic modeling could be combined with a deep learning model for automatic contouring and allow precise patient-specific dose adjustment in a non-invasive manner.

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Acknowledgements

Dr Anna Chan Kwong, Dr David Fabre, and all the Pharmacokinetics modeling and Pharmacometrics team (Sanofi Montpellier) for their advice on modeling and for the use of NONMEM license. Ms Souad Mekki and Ms Ikrame Berkane, Master degree students, for their help in data collection, image reconstruction, and contouring.

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Authors and Affiliations

  1. Pharmacokinetics and Pharmacometrics Department, School of Pharmacy, UFR Pharmacie, Montpellier University, 15 Avenue Charles Flahault, 34000, Montpellier, France

    Anissa Barakat & Sonia Khier

  2. Probabilities and Statistics Department, Institut Montpelliérain Alexander Grothendieck (IMAG), CNRS, UMR 5149, Inria, Montpellier University, Montpellier, France

    Anissa Barakat & Sonia Khier

  3. Nuclear Medicine Department, Montpellier Cancer Institute, Montpellier University, Montpellier, France

    Anissa Barakat, Lore Santoro, Pierre-Olivier Kotzki & Emmanuel Deshayes

  4. Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Montpellier University, Montpellier, France

    Lore Santoro, Pierre-Olivier Kotzki & Emmanuel Deshayes

  5. Biostatistics, Informatics and pharmaceutical physic Laboratory, School of Pharmacy, UFR Pharmacie, Montpellier University, 15 Av. Ch. Flahault, 34000, Montpellier, France

    Myrtille Vivien

  6. Institute of Functional Genomic (IGF)- UMR 5203, INSERM U1191, Montpellier, France

    Myrtille Vivien

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  1. Anissa Barakat
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  2. Lore Santoro
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Correspondence to Sonia Khier.

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All the authors declare that they have no financial nor non-financial interests that are directly or indirectly related to the work submitted for publication.

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Author contributions

AB extracted and collected the data, analyzed the data, analyzed literature, and wrote the initial draft of the manuscript. LS contributed to the literature search, data extraction, and writing of the manuscript. MV supervised the statistical analysis and reviewing the manuscript. POK contributed to reviewing the manuscript. ED contributed to data extraction, provided clinical input, and reviewed the manuscript. SK conceptualized the study, contributed to literature research, supervised the pharmacokinetic analysis, and wrote the manuscript.

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Barakat, A., Santoro, L., Vivien, M. et al. Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera®) Case. Eur J Drug Metab Pharmacokinet 48, 329–339 (2023). https://doi.org/10.1007/s13318-023-00829-5

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