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Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808, a small molecule nonpeptide selective somatostatin receptor 2 (sst2) agonist, is being evaluated for efficacy and safety in patients with acromegaly. The current Phase 1 study was conducted in two Parts: In Part A, the absorption, metabolism, excretion, and mass balance of a single oral dose of 20 mg [14C]-CRN00808 (3.0 MBq) oral solution was characterized in six healthy male subjects. Plasma, blood, urine, and feces were collected for up to 432 hours, and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Metabolite profiling was conducted on the plasma, urine, and feces samples. In Part B, the absolute bioavailability of CRN00808 was determined by administering a single oral dose of 20 mg CRN00808 compared with a single micro-tracer intravenous (IV) bolus injection of 50 µg [14C]-CRN00808 (0.0185 MBq) in five healthy male subjects. The IV dose was administered approximately 90 minutes after the oral dose. Plasma samples were collected for up to 144 hours and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Key data from Part A and Part B will be presented. Available data from Part A of the study show that >90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (<10%). Absorption of total [14C]-CRN00808-derived radioactivity in plasma was rapid (median Tmax=1 hour), and the mean Cmax, AUC0-∞, and t1/2 were determined to be 194 ng-equivalents/mL, 3340 ng-equivalents.hr/mL, and 31 hours, respectively. The pharmacokinetic parameters of unchanged CRN00808 in plasma were similar, suggesting that majority of the circulating drug-derived radioactivity is accounted for by unchanged CRN00808 and there are no abundant circulating metabolites. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this clinical trial in healthy volunteers confirm that CRN00808 has excellent drug-like properties for chronic once-daily oral treatment of patients with acromegaly.

journal of the endocrine society

OR23-05 Human Absorption, Metabolism, Excretion, and Absolute Oral Bioavailability of 14C-CRN00808, an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sST2) Biased Agonist for the Treatment of Acromegaly