Applications preclinical

Selective Genetics (San Diego, CA) Matrix-based delivery of DNA for various applications Preclinical... 

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. 

The area of racemic switches where a single enantiomer is developed subsequently to a corresponding racemate which is already on the market has attracted much interest [7, 8]. A description of the preclinical and clinical development of dexketoprofen provides a detailed example of one of these racemic switches [21]. The regulations in Europe and the US both allow for the development of a single enantiomer from a racemate by the use of bridging studies between the old and new applications. One problem to be considered is how a company which was not responsible for the original development can provide equivalent data. 

On the technical side, many different model building techniques are being explored and utilized. A fundamental constraint on the application of any model is the quality and availability of the data that it is built upon. In drug discovery, where the true data of interest (human in vivo parameters) are difficult to obtain and scarce, in vitro or preclinical in vivo experimental models are used to generate larger data sets and to guide decision-making. Most commonly, computational models are then used to predict these in vitro or preclinical endpoints. 

After completing preclinical testing, a company files an Investigational New Drug (IND) application with the regulators (the FDA in the U.S.), so that clinical studies in man can begin. The IND shows results of all experiments to this point, a detailed proposal for the clinical study, the expected mode of action for the drug, and any side effects observed. All clinical trials will also be reviewed and approved by the Institutional Review Board (IRB) at the clinic where the trials will be run. 

On completion of phase III trials, the data will be checked to see that it fulfils all the criteria required to generate a viable, marketable drag. The company will then file a New Drug Application (NDA), with the intention of proving the efficacy and safety of the drug in this therapeutic application. The NDA will contain all the clinical data and all relevant preclinical data for review by the FDA. Application reviews were 16.2 months on average in 1997 [75]. 

A series of indeno[l,2-c]isoquinolines have been described [27] and INO-lOOl has been investigated in the clinic. Although the structure of INO-lOOl has not been reported, sulfonamide 28 is a representative structure (IC50 = lnM, EC5O = 10nM). CEP-9722 is in Phase I clinical trials, while its exact structure has not been disclosed, it is a prodrug of CEP-8983 (29) and patent applications highlight 30. Preclinical efficacy in combination with TMZ and camptothecin have been... 

An investigational new drug is a new chemical-based, biologic or biopharmaceutical substance for which the FDA has given approval to undergo clinical trials. An IND application should contain information detailing preclinical findings, method of product manufacture and proposed protocol for initial clinical trials (Table 4.9). 

Upon completion of clinical trials, the sponsor will collate all the preclinical, clinical and other pertinent data (Table 4.10) and submit this to FDA in support of an application to allow the new drug to be placed upon the market. For CDER-related drugs, this submission document is termed an NDA. 

Some cytokines have already gained approval for medical use. Many more are currently undergoing clinical or preclinical trials. Over the next few chapters the biology and potential medical applications of these cytokines will be discussed in detail. The remainder of this chapter concerns itself with the prototypic cytokine family, namely the interferons. 

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