Use Of Systems Toxicology Modeling To Investigate Mechanisms Of Liver Enzyme Elevations Mediated By Solithromycin And Other Macrolides
Solithromycin, a 4th generation macrolide developed for the treatment of community acquired pneumonia, caused serum liver enzyme (ALT) elevations in clinical studies. A quantitative systems toxicology (QST) tool, DILIsym, was used to predict the occurrence and mechanisms of ALT elevations for solithromycin, erythromycin, clarithromycin, and telithromycin.
In vitro assays were performed to assess effects of the macrolides on bile acid transport, mitochondrial function, and oxidative stress. These data were integrated with in vivo exposure using DILIsym; serum ALT responses were predicted in a simulated human population.
DILIsym reasonably predicted the incidence of ALT elevations observed for solithromycin, erythromycin, and clarithromycin; the predominant mechanism was reversible mitochondrial electron transport chain (ETC) inhibition for solithromycin and clarithromycin, and bile acid transport inhibition for erythromycin. ALT elevations by Telithromycin were only predicted at the highest observed exposure combined with noncompetitive inhibition of bile acid transporters. CONCLUSION: Mechanisms for ALT elevations vary among macrolides, and solithromycin is similar to clarithromycin in this regard. The simulation results were presented to the FDA Advisory Committee for solithromycin on 11/4/16, a first to our knowledge for QST.
American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2017 Annual Meeting, March 15-18, 2017, Washington, DC
By Kyunghee Yang, Jeffrey L Woodhead, David Oldach, Chris MacLauchlin, Prabhavathi Fernandes, Paul B Watkins, Scott Q Siler, and Brett A Howell