Work

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

Year: 2025

Type: article

Abstract: Background/Aims: mice. Methods: 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. 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: 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.

Source: Gut and Liver

DOI: 10.5009/gnl250294