Regulatory Toxicological Studies: Identifying Drug-Induced Liver Injury Using Nonclinical Studies

Abstract

This chapter presents an overview of nonclinical safety assessment and the types of information that may be generated by drug developers for review by the US Food and Drug Administration (FDA). Every new drug molecule entering clinical development undergoes the process of safety assessment, a relatively standardized series of in vitro and in vivo examinations of the intrinsic properties of the proposed therapeutic. The goals are hazard characterization, identification of target organs, and determination of a theoretical margin of safety. These studies are usually conducted according to the guidances of the FDA and International Conference on Harmonization (ICH) and to a large extent conducted to the standards of Good Laboratory Practice. The ICH and FDA’s guidances allow investigators to modify safety assessment studies on a case by case basis when scientifically justified.

The components of nonclinical safety assessment include in vitro assessment of affinity for off-target receptors and enzymes, evaluation of the absorption, distribution, metabolism, and excretion (ADME), safety pharmacology, and repeat-dose animal studies and may include computer assisted analysis of the chemical structure. Standard in vivo toxicology studies alone are not sufficient to identify the potential for human drug-induced liver injury (DILI). A weight-of-evidence approach (WOE) is recommended. We discuss how each of the components of nonclinical investigation may be used in conjunction to help identify the potential for adverse hepatobiliary effects. Given the scientific flexibility offered by the FDA and ICH guidances, it is important to remember that repeat-dose animal studies may be modified to explore any identified safety signals. This allows for evaluation of possible reactive metabolites and other more subtle signals of drug-induced liver injury that might otherwise be missed in a standard single- or repeat-dose safety assessment study. Because of efforts to reduce, refine, and replace animal work, it becomes especially important to ensure that animal work is optimized. Judicious data-driven modification of the repeat-dose animal studies has the potential to increase the safety of clinical trial participants, to optimize the information obtained and to increase the translational value for the clinic.