Preclinical Toxicology

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. 

Drug synthesis------Acute and subacute toxicology-------- Preclinical trials ---- Phase I trials... 

The adverse reaction potential of an investigational new drug, to some extent, may be indicated by its molecular structural similarities to other drugs of known actions and by pharmacologic and toxicologic preclinical studies in appropriate species of laboratory animals. The full adverse reaction profile of a drug, how-... 

Hans-Jorg Martus, Ph.D. Head, Genetic Toxicology, Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland... 

Robertson, D. G., Watkins, P. B., and Reily, M. D. 2011. Metabolomics in toxicology Preclinical and clinical appheations. Toxicol. Sci. 120 S146-S170. 

Research Manager, Toxicology Preclinical Development RW Johnson Pharmaceutical Research Institute, USA... 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

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. 

The costs of drug development increase as a drug progresses through the development pipeline. Preclinical development is the time when chemical compounds are tested in the laboratory to learn as much as possible about how medicines work "in a test tube." These types of experiments can be done with many compounds in a relatively short time and with relatively low cost. This is also the time that animal testing begins to see whether the chemical compounds are safe. These studies help scientists to determine how medicines will be dosed in humans. They are also important to understand whether any toxicity is related to the medicines. Toxicological tests are time... 

Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines (CPMP/SWP/4654/95). June 1998. 

Bala, S., Weaver, J., and Hastings, K.L., Clinical relevance of preclinical testing for allergic side effects, Toxicology, 209, 195, 2005. 

Burchiel, S.W. and Weaver, J.L., Uses of Flow cytometry in preclinical safety pharmacology and toxicology, in Flow Cytometry for Biotechnology, Sklar, L.A., Ed., Oxford University Press, New York, NY, 2005, 275-290. 

Mangan FR, Flack JD, Jackson D. Preclinical overview of nabumetone. Pharmacology, bioavailability, metabolism, and toxicology. Am J Med 1987 83(4B) 6-10. 

During preclinical assessment of an enantiometric mixture, it may be important to determine to which of these three classes it belongs. The pharmacological and toxicological properties of the individual isomers should be characterized. The pharmacokinetic profile of each isomer should be characterized in animal models with regard to disposition and interconversion. It is not at all unusual for each enantiomer to have a completely different pharmacokinetic behavior. 

The kinds of information described here are found on three types of PC media floppy, CD-ROM, and laser disks. The products run the gamut of allowing one to assess current developments on a weekly basis, as well as to carry out more traditional reviews of historical information. The general types of information one can cover include basic pharmacology, preclinical toxicology, competitive products, and clinical safety. 

Hazelette, J., Thompson, T., Mertz, B., Vuolo-Schuessler, L., Gree, J., Tripp, S., Robertson, P. and Triana, V (1987). Rising dose tolerance (RDT) study A novel scenario for obtaining preclinical toxicology/drug metabolism data. Toxicologist 7, Abstract 846. 

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