Physiologically-based Pharmacokinetic Modelling for Optimising Photoactivated Curcumin Dosing in Antimicrobial-Resistant Infections

Abstract

Background: Photoactivated curcumin primarily exerts its therapeutic effects through the light-induced generation of reactive oxygen species (ROS), resulting in oxidative stress, mitochondrial apoptosis, and modulation of inflammatory pathways. This study aimed to develop whole-body physiologically based pharmacokinetic (PBPK) models to identify appropriate dosing regimens of photoactivated curcumin as an antimicrobial treatment for bacterial-resistant infections.

Methods: A whole-body physiologically based pharmacokinetic (PBPK) model was constructed using in vitro and human physiological parameters and validated against a clinical study of curcumin at oral doses of 4000, 6000, and 8000 mg. The verified model was used to simulate novel dosing strategies for photoactivated curcumin formulations. The rate of absorption and water-solubility properties influenced the once-daily and twice-daily oral dosing regimens of photoactivated curcumin. Considering long-acting intramuscular dosing, a weekly dose of 1500 mg with a first-order release rate from the intramuscular depot (K_im) of 0.012 /h and a weekly dose of 1250 mg with the Kim of 0.015 resulted in sufficient exposure. A daily dose of 200 mg with an infusion rate of 100 mg/h, twice-daily doses of 125 mg with an infusion rate of 250 mg/h, and three times-daily doses of 100 mg with an infusion rate of 200 mg/h provided satisfactory pharmacokinetic (PK) profiles.

Conclusion: PBPK modelling can be used as a tool to assist in dose optimisation strategies of photoactivated curcumin in various clinical conditions. The weekly intramuscular injection may improve compliance in diseases that require long-term treatment, thereby reducing selective pressure and drug resistance. The intravenous infusion could represent a suitable strategy for critically ill patients in the hospital.