Targeting assessment limitations

Reach target PK profile Reach target metabolic behavior, HTP phys-chem profiling Virtual screening HTP PK profiling Virtual screening Fast in vitro metabolic assessment Limited or dubious relevance of some HTP techniques Dubious predictive capacity of some models (see above) Limited or dubious in vivo relevance of some HTP screens Dubious predictive capacity of some models (see above) Dubious extrapolation to in vivo situation... 

The advantage of the basic targeting assessment lies in its simplicity it can be done quickly if the right data are available, it does not require exceptional analytic skills, and it produces results that are relatively easy to understand and interpret. However, this simplicity brings with it a number of limitations, some of which can be handled by more elaborated forms of targeting assessment (table 6.10). 

Superficial chemical peels, including salicylic and glycolic acids, and Jessner s peels target the stratum corneum to the papillary dermis. These agents can be safely used to facilitate the resolution of PIH (Figs. 16.2,16.3,16.4 and 16.5). To assess for variability in response and limit further PIH, when possible, chemical peels should be initiated at the lower concentrations and titrated to higher concentrations if necessary to increase efficacy while minimizing side effects (see Darker Skin Section). 

Measurement of exposure can be made by determining levels of toxic chemicals in human serum or tissue if the chemicals of concern persist in tissue or if the exposure is recent. For most situations, neither of these conditions is met. As a result, most assessments of exposure depend primarily on chemical measurements in environmental media coupled with semi-quantitative assessments of environmental pathways. However, when measurements in human tissue are possible, valuable exposure information can be obtained, subject to the same limitations cited above for environmental measurement methodology. Interpretation of tissue concentration data is dependent on knowledge of the absorption, excretion, metabolism, and tissue specificity characteristics for the chemical under study. The toxic hazard posed by a particular chemical will depend critically upon the concentration achieved at particular target organ sites. This, in turn, depends upon rates of absorption, transport, and metabolic alteration. Metabolic alterations can involve either partial inactivation of toxic material or conversion to chemicals with increased or differing toxic properties. 

Not only does the limited diversity of the compound database curtail the choice of lead, the process for assessing screening hits to see if they define a tractable lead is also limited by resources, particularly in those specialist assays that would predict the ability of the chosen lead class to successfully yield an approval in a particular therapeutic field. The process is therefore driven mainly by consideration of activity against the target. Therefore chemotypes with adequate but less than maximal potency for the target but freedom from damaging side activity remain undetected in this process. 

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