Dose-Response Relationship of Niclosamide and Metformin Combination in ApcMin/+ Mice: An Integrated In Vivo and Pharmacokinetic Modeling Study

Abstract

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 ApcMin/+ mice. ApcMin/+ mice were treated with metformin, niclosamide, or their combination at three doses (50, 100, and 200 mg/kg) for 16 weeks. The polyp burden was analyzed, and drug interactions were assessed by using the Bliss independence model to evaluate pharmacodynamic synergy and a physiologically based pharmacokinetic (PBPK) model to quantify the contribution of known pharmacokinetic interactions. 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. By integrating in vivo efficacy testing with quantitative modeling, our study identified the 100 mg/kg combination of niclosamide and metformin as the optimal dose for chemoprevention in a murine FAP model, providing a strong rationale for future clinical translation in FAP management.