Human biology-based drug safety evaluation: scientific rationale, current status and future challenges

ABSTRACT

Introduction: Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness.

Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted.

Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.

KEYWORDS:

• Adverse drug reactions
• liver injury
• cardiotoxicity
• in vitro assays

Article highlights

• Animal toxicity studies do not enable prediction of human idiosyncratic ADR risk posed by licensed drugs.

• Human idiosyncratic ADRs are initiated by chemical insults, which can be assessed using in vitro assays.

• Hence in vitro methods which address these initiating mechanisms can be used to identify drugs with high propensity to cause ADRs in the human population.

• Effective interpretation of in vitro assay data must take account of in vivo human drug exposure and requires integration of data from multiple assays.

However, in vitro assays cannot be used to assess ADR risk in individual human patients.

This box summarizes key points contained in the article.

Declaration of interest

Pharmaceutical Director of Safer Medicines Trust, which is an independent UK charity. Also an Independent Drug Safety Consultant, who provides paid advice to clients on drug safety and on methods that can be used to evaluate drug safety. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.