Preclinical lead profile

Genomics to Lead Development Candidate (Preclinical Lead Profile, PLP)... 

Dr. Laszlo Urban is currently Executive Director and Global Head of Preclinical Safety Profiling at Novartis Institutes for Biomedical Research. Dr. Urban has been actively involved in organizations such as the European Neuropeptide Club, the Society for Biomolecular Sciences, and the International Association for the Study of Pain. His most recently published work is Hit and Lead Profiling Identification and Optimization of Drug-Like Molecules (2009). 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

In the application described by Olah and workers, LC/MS-based methods are used to simultaneously assay plasma concentrations of up to 12 substances. The plasma is obtained from either single animals dosed with mixtures of lead compounds, or from multiple animals dosed with a single lead compound, after which aliquots of plasma from common time points are pooled. Essentially, simplified, less stringent versions of preclinical/clinical development procedures are used for sample preparation, assay validation, and analysis. A plasma concentration-time profile obtained from a dog administered simultaneously with 12 compounds is shown in Figure 6.21. Each... 

The principal issue in the drug discovery process is the high failure rate in the clinical trials, mainly due to liabilities related to poor pharmacokinetics (PK), poor efficacy, and high toxicity. The earlier lead optimization (LO) phase then represents a crucial step in the drug discovery process, since it involves the preparation and the selection of suitable drug candidates. In view of the increasing need for speed in the preclinical research and development, the determination of activity and selectivity is performed simultaneously with the evaluation of pharmacokinetic and toxicity properties. This multiparametric approach allows the early selection of the compounds with the best overall balanced druglike profile [1]. 

Many lead discovery candidates are transferred to the preclinical development process with insufficient characterization to assess their development potential. This lack of knowledge usually results in poorly designed experiments that are not data productive and that, in many cases, have to be repeated when a candidate shows unexpected toxicity, low and variable delivery, instability in formulation, or unacceptable pharmacokinetic and drug metabolism profiles. In all too many cases, the recognition of these problem areas results in termination of... 

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