Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model Page: 261

                                
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Prediction of Toxicity, Sensory Responses and
Biological Responses with the Abraham Model
William E. Acree, Jr.1, Laura M. GrubbsI and Michael H. Abraham2
'University of North Texas,
2University College London,
'United States
2United Kingdom
1. Introduction
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
adverse side effects account for up to two-thirds of drug failures.
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

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