Mechanistic Modeling Of Mitochondrial Biogenesis Within Dilisym Could Explain Clinically Observed Adaptation Of Serum Alanine Aminotransferase Elevations

Authors: Yang K, Ferdous J, Woodhead JL, Oldach D, MacLauchlin C, Fernandes P, Watkins PB, Howell BA, Siler SQ
Conference: SOT
Keywords: hepatotoxic potential, hepatotoxicity, mechanistic model, mitochondrial dysfunction, Quantitative Systems Toxicology (QST)
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Introduction

• Resolution of serum ALT elevations despite continued drug dosing, termed “adaptation”, is commonly observed in clinical trials, but the underlying mechanisms behind this phenomenon remain unclear.
• Mitochondrial dysfunction is one of the major mechanisms underlying drug-induced liver injury (DILI).[1] When mitochondrial function is insufficient for energy demand, mitochondrial biogenesis is often activated and contributes to adaptation.[2-4]
• Solithromycin, a 4th generation macrolide developed for the treatment of community acquired pneumonia, caused serum ALT elevations in a minority of patients in clinical studies, with improvement often observed during continued dosing (or with rapid recovery thereafter).[5]
• DILIsym® is a quantitative systems toxicology (QST) model which integrates in vitro mechanistic toxicity data, in vivo dynamic drug disposition, known biochemistry, and patient characteristics. DILIsym predicts the hepatotoxic potential of new drug candidates and also provides an enhanced understanding of the mechanisms underlying compounds that generate liver signals in the clinic. [6]
• QST modeling of five macrolide antibiotics using DILIsym showed that mechanisms underlying ALT elevations were significantly different within the same class of antibiotics. ALT elevations mediated by solithromycin and clarithromycin were predominantly due to mitochondrial electron transport chain (ETC) inhibition, whereas erythromycin effects were mainly due to bile acid (BA) transporter inhibition. Telithromycin and azithromycin hepatotoxicity was not explained by mechanisms represented in DILIsym (i.e., mitochondrial dysfunction, BA transporter inhibition, oxidative stress). [7]
• Mechanism analysis using QST modeling suggest that mitochondrial biogenesis might have contributed to the observed adaptation. In the current study, mitochondrial biogenesis was mechanistically represented within DILIsym, and its impact on time dependent ALT elevations resulting from solithromycin treatment was assessed.

Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas

By Kyunghee Yang, Jahid Ferdous, Jeffrey L Woodhead, David Oldach, Chris MacLauchlin, Prabhavathi Fernandes, Paul B Watkins, Brett A Howell, and Scott Q Siler