Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules

Francesco Cicone; David Viertl; Thibaut Denoël; Michael G Stabin; John O Prior; Silvano Gnesin

doi:10.1186/s13550-022-00893-z

Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules

EJNMMI Res. 2022 Apr 11;12(1):21. doi: 10.1186/s13550-022-00893-z.

Authors

Francesco Cicone^{1

2

3}, David Viertl⁴, Thibaut Denoël^{1

4}, Michael G Stabin⁵, John O Prior^{6

7}, Silvano Gnesin^{3

8}

Affiliations

¹ Department of Experimental and Clinical Medicine, and Neuroscience Research Centre, PET/MR Unit, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.
² Nuclear Medicine Unit, University Hospital "Mater Domini", Catanzaro, Italy.
³ University of Lausanne, Lausanne, Switzerland.
⁴ Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
⁵ NV5/Dade Moeller, Richland, WA, USA.
⁶ University of Lausanne, Lausanne, Switzerland. john.prior@chuv.ch.
⁷ Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland. john.prior@chuv.ch.
⁸ Institute of Radiation Physics, Lausanne University Hospital, Lausanne, Switzerland.

Abstract

Background: Extrapolation of human absorbed doses (ADs) from biodistribution experiments on laboratory animals is used to predict the efficacy and toxicity profiles of new radiopharmaceuticals. Comparative studies between available animal-to-human dosimetry extrapolation methods are missing. We compared five computational methods for mice-to-human AD extrapolations, using two different radiopharmaceuticals, namely [¹¹¹In]CHX-DTPA-scFv78-Fc and [⁶⁸Ga]NODAGA-RGDyK. Human organ-specific time-integrated activity coefficients (TIACs) were derived from biodistribution studies previously conducted in our centre. The five computational methods adopted are based on simple direct application of mice TIACs to human organs (M1), relative mass scaling (M2), metabolic time scaling (M3), combined mass and time scaling (M4), and organ-specific allometric scaling (M5), respectively. For [⁶⁸Ga]NODAGA-RGDyK, these methods for mice-to-human extrapolations were tested against the ADs obtained on patients, previously published by our group. Lastly, an average [⁶⁸Ga]NODAGA-RGDyK-specific allometric parameter α_new was calculated from the organ-specific biological half-lives in mouse and humans and retrospectively applied to M3 and M4 to assess differences in human AD predictions with the α = 0.25 recommended by previous studies.

Results: For both radiopharmaceuticals, the five extrapolation methods showed significantly different AD results (p < 0.0001). In general, organ ADs obtained with M3 were higher than those obtained with the other methods. For [⁶⁸Ga]NODAGA-RGDyK, no significant differences were found between ADs calculated with M3 and those obtained directly on human subjects (H) (p = 0.99; average M3/H AD ratio = 1.03). All other methods for dose extrapolations resulted in ADs significantly different from those calculated directly on humans (all p ≤ 0.0001). Organ-specific allometric parameters calculated using combined experimental [⁶⁸Ga]NODAGA-RGDyK mice and human biodistribution data varied significantly. ADs calculated with M3 and M4 after the application of α_new = 0.17 were significantly different from those obtained by the application of α = 0.25 (both p < 0.001).

Conclusions: Available methods for mouse-to-human dosimetry extrapolations provided significantly different results in two different experimental models. For [⁶⁸Ga]NODAGA-RGDyK, the best approximation of human dosimetry was shown by M3, applying a metabolic scaling to the mouse organ TIACs. The accuracy of more refined extrapolation algorithms adopting model-specific metabolic scaling parameters should be further investigated.

Keywords: Allometric equations; Biodistribution; Dose extrapolations; Mass scaling; Metabolic time scaling; OLINDA/EXM® 2.0; Preclinical models; Radiopharmaceuticals; Scaling factor; Small animal dosimetry.

Grants and funding

(642889 MEDICIS-PROMED)/Horizon 2020