Abstract
ObjectiveAstatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose.Methods[211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.ResultsNo abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt.ConclusionsIn the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.
Highlights
Materials and methodsIn recent years, radionuclide therapy is attracting attention for the treatment of various types of cancers
We are preparing for an investigatorinitiated clinical trial of targeted alpha therapy for differentiated thyroid cancer refractory to standard 131I treatment or tyrosine kinase inhibitor, in consultation with the Pharmaceuticals and Medical Devices Agency (PMDA), the Japanese authority for drug approval
A significant decrease in body weight was observed on days 3 and 5 in the male 50 MBq/kg group (5 days monitoring; p = 0.016 and p = 0.021, respectively) and on day 3 in the male 50 MBq/ kg group (14 days monitoring; p = 0.003) compared to that of the control group (Fig. 1)
Summary
Radionuclide therapy is attracting attention for the treatment of various types of cancers. The current study is an extended single-dose toxicity examination using mice with reference to the ICH guidelines and previous reports, which was performed in accordance with the reliability standard as a preclinical safety assessment of [211At]NaAt to determine the FIH dose [4,5,6,7]. For the control and 50 MBq/kg group, the brain (cerebrum), thyroid gland (including epithelial body), trachea, esophagus, salivary gland (sublingual gland/submandibular gland), thymus, heart, lung (including bronchi), liver and gallbladder, pancreas, stomach, jejunum, duodenum, colon, mesenteric lymph node, spleen, kidney, adrenal gland, bladder, testis, ovary, uterus, bone and bone marrow (femoral bone), eyeballs, as well as other organs and tissues with macroscopic changes, were examined. Statistical analyses were carried out using SPSS (version 19.0), and statistical significance was set at p < 0.05
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