Selection of Relevant Species

1 Species Selection Biologies versus Small Molecule Therapies 182 

5 Ex vivo / In vitro Interaction of the Biopharmaceutical with Known 

1 Binding Assays Flow Cytometry Based Methods 194 

1 Sequence Homology of Target Protein in Various Species 199 

The goal of biopharmaceutical development is to maximize therapeutic benefit while minimizing the risk of treatment-related toxicity. To mimic putative interpatient treatment differences in test article responsiveness, it is important 

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Subramanyam M, Rinaldi N, Mertssching E, Hutto D. Selection of relevant species. (In Cavagnaro JA, ed. Preclinical Safety Evaluation of Biopharmaceuticals. John Wiley Sons Inc. Hoboken, New Jersey. 2008 9 181-206. 

General applicability of cmitrolled-potential coulometry (CPC) has been utilized in the analysis of inorganic substances, individually or sequentially, due to convenience and high accuracy. Furthermore, precious metals are determined by CPC. High selectivity of relevant species is achieved based on the relative position of redox potential in order to the accompanying interferents [3]. The employment of CPC is also performed to the synthesis of organic compounds [4], in which the quantity of redox electrons (i.e., electron-transfer numbers) is accurately measured [5-7]. 

Animal Species/Model Selection. Safety evaluation should include the use of relevant species, in which the test article is pharmacologically active due, for example, to the expression of the appropriate receptor molecule. These can be screened with in vitro rector binding assays. Safety evaluation should normally include two appropriate species, if possible and/or feasible. The potential utility of gene knockout and/or transgenic animals in safety assessment is discussed. 

Ducrot, V., Usseglio-Polatera, P., Peiy, A.R.R., Mouthon, M., Laffont, M., Roger, M.C., Garric, J. and Ferard, J.F. (2005) Functional grouping based on species traits contribution to improvement of relevance in the selection of test species for ecotoxicology, Environmental Toxicology and Chemistry (in press). 

Selection of relevant rodent and nonrodent species for preclinical testing... 

This chapter will discuss various experimental approaches used to select the relevant species for conduct of toxicology studies for biopharmaceuticals, as well as highlight advances made in scientific approaches and technologies to facilitate this process. Methods discussed include the traditional immunohisto-chemistry and tissue cross-reactivity studies, flow cytometry, protein sequencing, and functional in vitro assays, as well as newer approaches such as utilization of microarray databases for genomic mRNA expression data and use of transcript profiling studies as an adjunct to functional assays, to understand similarity in pharmacological responsiveness between animals and humans. 

Figure 9.1 Proposed rank ordering of methods informing species selection for safety assessment of biopharmaceuticals. Various methods used for selecting pharmacologically relevant species for toxicological studies of biopharmaceuticals are presented, ordered (top to bottom) by the extent to which the data might impact the decision on which species to use. In cases where the methods are further discussed in this chapter, the relevant figure/table numbers are provided. These types of analyses may also be used for creating data packages for small molecules, although not typically for species selection.

Tissue Cross-Reactivity Studies for Monoclonal Antibodies Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing... 

The Role of Pharmacokinetics and Pharmacodynamics in Selecting a Relevant Species... 

Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model, pharmacokinetic profile, species, strain, gender, and age of the experimental animals, the susceptibility, sensitivity, and reproducibility of the test system and available background data on the substance. Data from humans (e.g., in vitro metabolism), when available, should also be considered in the test system selection. 

The detailed mechanism and relative energetics for the loss of the HD in the reaction of PtAuCD2" with NH3 are shown in Fig. 22. Selected optimized structures of relevant species in the reaction are collected in Fig. 23. NBO analyses indicate that the N-Pt bond in 12 arises from strong donor-acceptor interactions of the lone pair of NH3 with an antibonding orbital of the PtC subunit. The N-C bond coupling through migration of NH3 to C produces an intermediate 14 with a barrier of... 

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