Building a Tiered Approach to In Vitro Predictive Toxicity Screening: A Focus on Assays with In Vivo Relevance

James Mckim Jr

doi:10.2174/138620710790596736

Abstract

One of the greatest challenges facing the pharmaceutical industry today is the failure of promising new drug candidates due to unanticipated adverse effects discovered during preclinical animal safety studies and clinical trials. Late stage attrition increases the time required to bring a new drug to market, inflates development costs, and represents a major source of inefficiency in the drug discovery/development process. It is generally recognized that early evaluation of new drug candidates is necessary to improve the process. Building in vitro data sets that can accurately predict adverse effects in vivo would allow compounds with high risk profiles to be deprioritized, while those that possess the requisite drug attributes and a lower risk profile are brought forward. In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity. However, when used in a prospective manner, they have not been highly predictive of in vivo toxicity. Therefore, the issue may not be how to collect in vitro toxicity data, but rather how to translate in vitro toxicity data into meaningful in vivo effects. This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

Highlights

AND RATIONALE FOR IN VITRO TOXICITY SCREENINGThe discovery and development of a new pharmaceutical drug requires more than a billion dollars and can take 12 years of research effort
Drugs and chemicals can affect cell health at multiple levels at varying exposure concentrations and after different times of exposure. This means that certain subcellular targets such as mitochondrial function may be significantly affected before the cell dies and releases marker enzymes for viability into the media
These endpoints would have provided a more accurate assessment of the toxic liability associated with rotenone; it would not be apparent from just these data whether the effects were due to cell death, changes in cell proliferation, or inhibition of the enzymes essential for assay performance

Summary

Introduction

The discovery and development of a new pharmaceutical drug requires more than a billion dollars and can take 12 years of research effort. New chemical entities or NCEs can be dropped from development for many reasons during this process, and the attrition rate for NCEs during preclinical and clinical studies is higher than it has been in decades. It has been estimated that only 1 of 10,000 chemicals that enter the discovery process ever reaches the market This is not hard to imagine when one considers that 40% of NCEs that begin preclinical safety studies in animals will fail due to toxicity, and that 89% of NCEs that enter clinical trials will fail. The greatest cost in terms of time occurs in early and late discovery, which can require 6 to 8 years of research effort. The ability to identify and reduce risk early can significantly improve the process of drug development by improving efficiency and improving the probability of success

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