Dose-Response Relationship of Niclosamide and Metformin Combination in Apc

Background/Aims: Familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome caused by APC gene mutations, is characterized by the development of numerous colorectal polyps and cancer at young age. To determine an effective chemopreventive strategy, we investigated the combined effects of varying doses of niclosamide and metformin in Apc Methods: Apc Results: Low-dose metformin (50 mg/kg), niclosamide (50 mg/kg), and their combination showed no significant effects on the total polyp numbers compared with those in the control group. Higher doses (100 and 200 mg/kg) of both agents and their combination significantly reduced the total polyp numbers. The Bliss independence model showed a significant additive effect at the 100 mg/kg combination dose, whereas at the 200 mg/kg combination dose, an antagonistic interaction was observed. PBPK modeling predicted that coadministration of niclosamide increased exposure to metformin. Notably, the predicted metformin plasma Cmax remained within a safe therapeutic window at the 100 mg/kg combination dose but exceeded a safety threshold at 200 mg/kg. Conclusions: By integrating