Vivo Studies — Preclinical Toxicology

Before any agent can enter into first-in-human studies, a battery of preclinical toxicological studies are required. The major goals of these preclinical 

In 1980, the European Organization for Research and Treatment of Cancer (EORTC) adopted more 

In the United States, the FDA has issued guidelines that make specific recommendations for the non-clinical pharmacology and toxicology sections of an Investigational New Drug application (IND). These guidelines are available on the FDA web site (http // www.fda.gov/cder/PharmTox/guidances.htm). 

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Kanter PM, Bullard GA, Pilkiewicz FG, Mayer LD, Cullis PR, Pavelic ZP. Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99) comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo 1993 7(l) 85-95. 

The objectives of the preclinical safety studies are to define pharmacological and toxicological effects not only prior to initiation of human studies but throughout clinical development. Both in vitro and in vivo studies can contribute to this characterisation. Biopharmaceuticals that are structurally and pharmacologically comparable... 

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. 

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