Preclinical and clinical toxicology

Preclinical and Clinical Toxicology of Selected Retinoids Jerome J. Kamm, Kathleen O. Ashenfelter, and Carl W. Ehmann... 

The high attrition rate of new chemical entities (NCEs) in preclinical and clinical phases can be attributed to many factors. According to Kola and Landis [50], NCEs fail mainly to insufficient efficacy, bioavailability, safety, toxicological and economic reasons. All these factors are somehow interrelated - a less soluble drug might be less bioactive and thus less efficient. Additionally, the attrition rate can depend on the therapeutic area the drug comes from. For example, compounds tend to fail more for CNS and oncology indications than in other therapeutic areas [50]. 

Preclinical and clinical process laboratories serve a critical function in the development and organization of toxicology data, animal testing results, and ultimately of human test results. Again, the GLPs provide guidance and assure both minimization of misinterpretation and control of both the potential risks to human subjects and the suffering of test animals. 

At present, tasidotin is still in development, and questions regarding its pharmacokinetic and mechanism of action remain unanswered, but that is the nature of drug development. As new data become available, new questions arise such that, at the time of regulatory approval, the sponsor should have a clear understanding of the mechanism of action, relationship between toxicology, preclinical and clinical pharmacokinetics, and the safety and efficacy of the drug. 

In silico tools make a significant contribution to the SAR-based early identification of potential toxicity. An increasing volume of published preclinical and clinical toxicity data are collected and used to build structure-related searchable databases. These expert knowledge databases can analyze chemical structures and match them with potential mechanisms of toxicity. DEREK for Windows (Lhasa Ltd.)39 is one of such broadly used knowledge-based expert systems to provide toxicology alerts for new compounds. Although certainly not comprehensive, numerous efforts have been made to predict hepatotoxicity. Recently,... 

A few decades ago, pharmacokinetics, drug metabolism, and toxicology of selected clinical candidates were studied mainly during preclinical and clinical develop-... 

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

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