Early Human Toxicity Screening Strategies during Drug Discovery in the 21st Century to prevent Adverse Drug Reactions
G Praveen Kumar,
Professor & Principal,
Sahasra Institute of Pharmaceutical Sciences
One of the major stumbling blocks in the success of drug development continues to be the less than optimal prediction of potential human drug toxicity both during the early discovery phase as well into late stage clinical trials. This continues to be a major area of discussion in the fields of drug metabolism and toxicology particularly as it pertains to interspecies extrapolations from non-clinical animal studies. As drugs are usually foreign chemicals, concern for the biotransformations of drugs leading to toxic metabolites formation is intrinsically linked to the history of xenobiotic metabolism studies. The basic understanding of many of the human P450s is relatively well established in terms of the details of the individual genes, sequences and basic catalytic mechanisms. During the past 20 years, we have seen a major shift of emphasis to human P450s which had seemed almost impossible in the early research. Even though significant advancements have been made in establishing a clearer definition of benefit and risk for most medications, adverse drug reactions (ADRs) continue to be a major cause of morbidity and mortality worldwide. It is now time to invest in and develop an innovative and comprehensive strategy for predicting human drug toxicity and safety throughout the drug discovery and development process. The strategy must include a substantial level of data transparency which would allow us to gain from a wealth of experience from academic, industry and governmental sources. The new system we envision must include chemical motif predictions and metabolic estimates from expert systems, incorporate information on potential patient populations and potential susceptible individuals and must continually incorporate knowledge from new technologies and innovations. There is widespread agreement that ADRs continue to be an enormous public health problem. It is also interesting to develop different types of technologies that could be used to create specific anima
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