Preclinical assessment

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. 

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. 

Stebbing, N. and Week, P.K. (1984). Preclinical assessment of biological properties of recombinant DNA-derived human interferons. In Recombinant DNA Products Insulin, Interferon and Growth Hormone, (Bollon, A.P., Ed.). CRC Press, Boca Raton, FL. 

However, for general preclinical assessments and screening purposes, in vitro tests should be well validated and used cautiously for several reasons. 

An evaluation of the various studies reported in the literature for preclinical assessment of drugs for nasal administrations indicated the usefulness of in situ, ex vivo, and in vivo approaches. Evidence from the literature also indicates that the choice of a particular model or animal species by different... 

Kalman D (2002) The subjective effects of nicotine methodological issues, a review of experimental studies, and recommendations for future research. Nicotine Tob Res 4 25-70 Katz JL, Goldberg SR (1988) Preclinical assessment of abuse liability of drugs. Agents Actions 23 18-26... 

The preclinical assessment for the safety of potentially new pharmaceuticals represents a special case in the general practice of toxicology. This phase has its own peculiarities and considerations and differs in several ways from the practice of toxicology. Pharmaceuticals, unlike industrial chemicals, agriculture chemicals, or environmental agents, are intended for human use and systemic exposure. Therefore, pharmaceuticals are specific in action and have biological effects on those treated for different diseases. 

In contrast to chemicals, biomaterial and medical device testing constitutes an extremely diverse, heterogeneous category of evaluation. Because the use of these products normally entails direct or indirect contact with patients, there is an obligation for manufacturers to establish the product s safety before marketing. Medical device safety evaluation assesses the risk of adverse effects due to normal use and misuse. Since adverse effects could result from exposure to the materials from which a device is made, preclinical assessment is needed to minimize the potential hazard to the user, namely, the patient. 

Species specificity Species independent preclinical assessments for generally toxicity generally performed in one rodent (generally rat) and one nonrodent (generally dog) Species specific nonhuman primates often the only relevant species or design of specific animal models... 

Hayes TJ, Cavagnaro JA. Progress and challenges in the preclinical assessment of cytokines. Toxicol Letts 1992 64/65 291-7. 

TABLE 19.4a Examples of communication of human carcinogenic risk without preclinical assessment of carcinogenic risk... 

As mentioned above, preclinical pharmacology and toxicology for plasma derivatives has not included preclinical assessments commonly employed for small-molecule drug products. Most preclinical development involves comparative pharmacokinetics and the use of animal models has been an important component of this evaluation. The coagulation factors have shown the potential for efficacy in animal models such as the von Willebrand swine and hemophilic dog [16,17],... 

The preclinical assessment of blood products has been based on studies designed to answer specific questions on product-specific attributes with a consideration of the intended patient population. In many cases relevant animal models of the disease have been used to assess safety in addition to providing proof-of-concept information to support clinical development. 

Finally, a major challenge for both developers and regulators of biologic-device combination products is the potential need to reconsider the way that certain key parameters typically associated with preclinical assessment, such as dose in the case of the biologic and durability in the case of the device, are defined, measured, and analyzed. 

While good scientific principles should always be applied to preclinical assessments of biopharmaceuticals, practical considerations for the implementation of said methods should be given equal consideration when designing and conducting these studies. Some of these considerations are the subject of this chapter and will be discussed briefly mainly through tabular illustration. 

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