Nonclinical safety assessment for therapeutic radiopharmaceutical development: a scoping review of rodent studies

Therapeutic radiopharmaceuticals enable target-directed radiation delivery and are increasingly important in translational cancer research. However, nonclinical safety data remain difficult to interpret across studies because clinical pathology and histopathology endpoints are selected, timed, and reported inconsistently. This scoping review aimed to characterize the use of pathology-related endpoints that are used in rodent studies of therapeutic radiopharmaceuticals and to identify reporting gaps relevant to more interpretable nonclinical safety assessments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidance, PubMed was searched for in vivo rodent studies of therapeutic radionuclides or radiopharmaceuticals that reported clinical pathology and/or histopathology endpoints. Data were charted descriptively with emphasis on study characteristics, endpoint selection, organ evaluation, observation period, and pathology-informed interpretation. Seventy-five studies were included in total. Clinical pathology was reported in 68 studies and histopathology in 51, whereas only 29 reported hematology, blood chemistry, and histopathology together. White blood cell (WBC) and platelet counts were the most frequently reported hematology parameters, whereas blood urea nitrogen (BUN) and creatinine (Crea) were the most frequently reported blood chemistry parameters. The kidneys were both the most commonly examined organs and the most frequent sites of reported lesions, including tubular epithelial karyomegaly, glomerulosclerosis, tubular dilatation, and interstitial fibrosis. Observation periods ranged from 4 d to 52 weeks and varied widely both within and across radionuclide groups. Reported activity ranges associated with intolerance varied widely across radionuclides and study designs, and several radionuclides lacked extractable or clearly defined activity levels associated with intolerance. Nonclinical safety studies of therapeutic radiopharmaceuticals revealed recurring patterns of hematologic suppression and renal injury; however, substantial heterogeneity in endpoint selection, organ evaluation, follow-up design, and tolerability reporting limited cross-study interpretability. The mapped evidence supports a more explicit minimum reporting framework for clinical pathology, histopathology, organ selection, follow-up duration, and pathology-based tolerability assessment in therapeutic radiopharmaceutical development.