The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--Pharmaceuticals: An Efficient and Humane Approach to Predictors of Potential Toxic Effects of Drugs

Tiered Approaches To Toxicity Testing: Pharmaceutical Industry Initiatives In Implementing The 3Rs

Oliver P. Flint
Drug Safety Evaluation, Bristol-Myers Squibb

Drug development involves risk, financial risk in the event of failure and human risk in the event of unforeseen adverse effects. Managing this risk is increasingly important from a competitive point of view. Significantly greater numbers of compounds are synthesized each year to meet program demands for accelerated discovery, increasing the need for more and better tests to screen out potential failures. Two major factors drive the choice of predictive test, the number of compounds to be tested and the availability of compound for the test. At the earliest stage of drug discovery, prior to a program of compound synthesis, computational methods are used to design drug-like molecules. Software solutions are also available to examine molecular structure and predict toxicity associated with specific structural fragments. Commercially available programs have significant limitations, but when these limitations are understood and the right mix of programs is used, there is significant value in using these programs to predict toxicity. These computational assessments are insufficient on their own for decision-making and should be confirmed in a process of tier testing, first by simple in vitro tests, then by more complex in vitro tests, and finally by in vivo studies. Simple in vitro tests are normally used at a time of higher throughput and low compound availability. More complex in vitro tests generally require greater amounts of compound but also provide more precise predictions that are useful at later stages of discovery. Many types of test are available, predicting a wide range of toxicities, including the most important causes of drug development failure: genetic damage, liver toxicity, reproductive toxicity, prolonged QT-interval, poor bioavailability, inappropriate interaction with drug-metabolizing enzymes. Some of the test methods are old and well established, some old but still little used, and some new and poorly understood. This presentation will describe a paradigm for management of risk in drug development that combines a variety of testing methods into a structured tier testing approach to the prediction of safety.

Slides