In vitro to in vivo extrapolation for drug-induced liver injury using a pair ranking method.

Zhichao Liu

doi:10.14573/altex.1610201

Abstract

Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours. Notably, a pair ranking (PRank) method was developed to assess IVIVE potential with a PRank score based on the preservation of the order of similarity rankings of compound pairs between the platforms using a receiver operating characteristic (ROC) curve analysis to measure area under the curve (AUC). A high IVIVE potential was noted for rat primary hepatocytes when compared to rat 28-day studies (PRank score = 0.71) whereas the IVIVE potential for human primary hepatocytes compared to rat 28-day studies was lower (PRank score = 0.58), indicating that species difference plays a critical role in IVIVE. When limiting the analysis to only those drugs causing drug-induced liver injury, the IVIVE potential was slightly improved both for rats (from 0.71 to 0.76) and for humans (from 0.58 to 0.62). Similarly, PRank scores were improved when the analysis focused on specific hepatotoxic endpoints such as hepatocellular injury, or cholestatic injury. In conclusion, toxicogenomic data generated in vitro yields a ranking of drugs regarding their potential to cause toxicity which is comparable to that generated by in vivo analyses.

Highlights

Before a potential new medicine can progress to clinical trials in humans, it must be assessed for safety and tolerability in both rodent and non-rodent toxicology studies to limit and manage risk to human volunteers and patients
We examined in vitro to in vivo extrapolation (IVIVE) potential by assessing the similarity of gene activities between in vitro and in vivo TGx systems using Open TGGATEs, a TGx database that stores gene expression profiles and traditional toxicological data derived from in vivo and in vitro studies on 131 compounds at multiple doses/concentrations and time points
Pair ranking (PRank) method In order to study the IVIVE potential in TGx, we developed a pair ranking (PRank) method including the following steps: 1) We first ranked genes by fold change for each compound

Summary

Introduction

Before a potential new medicine can progress to clinical trials in humans, it must be assessed for safety and tolerability in both rodent and non-rodent toxicology studies to limit and manage risk to human volunteers and patients. This current paradigm is based on law and on historical data that show a concordance of the toxicity of pharmaceuticals in humans and animals (Olson et al, 2000). In addition to questions on the correlation between animal models and human toxicity, worldwide efforts are being made to reduce animal testing and to enhance safety assessment largely based on developing in vitro systems or in silico approaches tailored to toxicologically relevant mechanisms. In the United States, there are several relevant programs such as “Advancing Regulatory Science” initiated by the Food and Drug Administration (FDA) (Hamburg, 2011), the Toxicology in the 21st Century (Tox21) program led by multiple governmental agencies (Tice et al, 2013) and the ToxCast program (Dix et al, 2007) developed by the U.S Environmental Protection Agency

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