Utility of Preclinical Dosimetry for First-in-Human Studies with PET Drugs Labeled with Common Radionuclides: A Systematic Review of Radiation Dose Estimates

First-in-human studies of radiopharmaceuticals include an estimation of human radiation doses often extrapolated from preclinical biodistribution data. We reviewed radiation dose estimates derived from preclinical and clinical studies to determine the utility of preclinical dosimetry studies for estimating the human radiation dose of PET radiopharmaceuticals. <b>Methods:</b> Literature searches were performed for preclinical and clinical studies published between 1990 and 2021 that provided radiation dose estimates for common PET radiopharmaceuticals. Whole-body effective dose and maximum organ absorbed dose coefficients derived from animal and human studies were compared to evaluate their agreement. Ratios of animal-derived to human-derived dose estimates were calculated. Dosimetry data were further stratified by pharmacophore, animal species, and animal-to-human extrapolation method. <b>Results:</b> The SD in radiation dose estimates from clinical studies was generally lower compared with the SD in dose estimates extrapolated from animals. An overlap in the distribution of radiation dose estimates derived from animal and human studies was observed for short-lived radiopharmaceuticals (⁸²Rb-, ¹⁵O-, ¹³N-, ¹¹C-, ⁶⁸Ga-, ¹⁸F-, and ⁶⁴Cu-labeled, <i>n</i> = 394). The higher dose estimates and larger variability (spread) in preclinical and clinical radiation dose estimates observed for long-lived (⁸⁹Zr- and ¹²⁴I-labeled, <i>n</i> = 48) compared with short-lived radiopharmaceuticals highlight important differences in the radiation profile between the 2 groups. <b>Conclusion:</b> Our assessment of the agreement between animal and human radiation dosimetry data for PET drugs indicated a difference between short-and long-lived radiopharmaceuticals in terms of agreement, magnitude, and variability in dose estimates. A closer agreement between animal and human data, relatively lower doses, and lower variability in measured ED values in studies of short-lived PET radiopharmaceuticals suggest that approaches to forego preclinical dosimetry can be developed to facilitate clinical trials of new PET drugs for certain short-lived radionuclides. For first-in-human studies of long-lived PET radiopharmaceuticals or radiopharmaceuticals with long biological turnover, which are associated with higher radiation doses, animal-derived human dose estimates may provide necessary radiation safety information (e.g., identify unexpected high uptake in a particular organ) even though the radiation dose may be underestimated.