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**12** 

*1University of North Texas, 2University College London,* 

> *1United States 2United Kingdom*

**Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model** 

Modern drug testing and design includes experimental *in vivo* and *in vitro* measurements, combined with *in silico* computations that enable prediction of the drug candidate's ADMET (adsorption, distribution, metabolism, elimination and toxicity) properties in the initial stages of drug discovery. Recent estimates place the discovery and development cost of a small drug molecule close to US \$1.3 billion, from the time of conception to the time when the drug finally reaches the market place. Less than one-fourth of conceived drug candidates proceed to clinical trial stage testing, and of the compounds that enter clinical development less than one-tenth actually receive government approval. Reasons for the low success percentage include poor efficacy, low solubility, unsatisfactory bioavailability, unfavorable pharmacokinetic properties, toxicity concerns and drug-drug interactions, degradation and poor shelf-life stability. Unfavorable pharmacokinetic and ADME properties, toxicity and

Safety evaluation of drug candidates is crucial in the early stages of drug discovery and development. For drug development, safety requires that the potential drug molecule have sufficient selectivity for the desired target receptor so that an adequate dose range can be found where the intended pharmacological action is essentially the only physiological effect exhibited by the drug candidate. Pharmaceutical compounds often exhibit the desired therapeutic action at one concentration range, but may be quite toxic or even lethal at higher dosages and concentrations. Drug induced liver injury (DILI) is the most frequent reason for discontinuation of new drug candidates. Drug-induced liver injuries are classified as predicted/intrinsic or idiosyncratic depending upon whether the injury is dose dependent. Predictable DILIs are dose-dependent, and the injury is largely reversible once the medication is discontinued. Idiosyncratic DILIs, on the other hand, are independent of drug dosage level and believed to be related in part to individual's hypersensitivity or immune system reactions to the medication. Idiosyncratic DILIs depend upon the individual's potential genetic and epigenetic constitution, and immunological responses (Ozer *et al*., 2010). Examples of drug and/or drug candidates that either failed in late stage clinical testing or were removed from the market because of drug-induced liver injury concerns include: ximelagatran (an anticoagulant that was promoted extensively as a replacement for

adverse side effects account for up to two-thirds of drug failures.

**1. Introduction** 

William E. Acree, Jr.1, Laura M. Grubbs1 and Michael H. Abraham2

D. S. (2009). Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. *Hum Mol Genet, 18*(22), Nov 15,pp. 4390-4404

