Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

Authors: Woodhead JL, Paech F, Maurer M, Engelhardt M, Schmitt-Hoffmann AH, Spickermann J, Messner S, Wind M, Witschi AT, Krähenbühl S, Siler SQ, Watkins PB, Howell BA
Publication: Clin Transl Sci
Keywords: drug-induced liver injury, electron transport chain (ETC), hepatotoxicity, in vitro, liver enzymes, quantitative systems pharmacology (QSP) model
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Abstract

Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low. DILIsym was then used to recommend potential modifications to this dosing scheme; weight-adjusted dosing and a requirement to assay plasma alanine aminotransferase (ALT) daily and stop dosing as soon as ALT increases were observed improved the predicted safety margin of BAL30072 and decreased the predicted likelihood of severe injury. This research demonstrates a potential application for QSP modeling in improving the safety profile of candidate drugs.

By Jeffery Woodhead, Scott Q Siler, Paul B Watkins, Brett A Howell