The Need for Prediction

As ADME/PK has become incorporated into drug discovery it has become necessary to reconsider the purpose of the studies. If the science is really going to reduce the attrition rate in development, then it is essential for the studies to allow predictions of the PK in man to be made. This means predicting the likely size and frequency of the dose. A review of the top 10 medicines of 1999 (Table 6.1) shows all of them to be once-a-day compounds. It is clear that to be best in class , and to be able to maintain that position as follow-up compounds come along, it seems probable that a compound will need to be suitable for once a day dosing. 

Although the pressure to screen large numbers of compounds quickly has led to the rapid development of in silico and in vitro assays, the sheer number and complexity of the processes involved in determining the disposition of any particular compound means that in vivo studies are still required to provide assurance that the important processes are modeled with sufficient accuracy [4-6], and indeed, that the potential contribution of processes for which there are no good in vitro models (e.g., biliary secretion) are adequately assessed. 

Although prediction of ADME/PK in man may be the primary purpose for the pre-clinical studies, it is also important that potential new drugs have acceptable properties in toxicology species. Without these it can be very difficult to generate adequate safety margins to allow studies in man to start. It is also likely that the development safety assessment program will be difficult and hence slow. 

Product Indications 1999 sales [Sbillion] %Clobal Sales Launched Dosing regime 

Losec (omeprazole) Duodenal ulcer Gastro-oesophageal reflux Helicobacter infections 5.7 1.9 1989 - UK and US Once daily, except when used as part of combination therapy 

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Such essential limitations may markedly decrease the reliability and predictive capacity of quantitative structure-toxicity relationships (STRs) in haloalkenes and all other classes of toxic xenobiotics, but recognition of limitations does not suppress the need for predictive tools. In fact, any approach, empirical or mechanistic, that is able to uncover qualitative STR trends and to assign a priori labels of potential toxicity is certainly welcome. 

For exposure to multiple chemicals, PBPK modeling is further limited as a predictive tool, as all interactions among the various chemicals within the organism must be known and incorporated into the model. Difficulties in multiple-chemical exposure are clearly illustrated in drug-drug and drug-food interactions, where one substance affects the pharmacokinetics or pharmacodynamics of another. To address the need for predictive capability for individual and mixtures of chemicals, new advances and approaches are required. Biochemical reaction network modeling is one nascent approach, as described in Section 3.4. 

As we discussed earlier, the need for predictions of spatial and temporary concentration distributions is driven by regulatory requirements. For the example of the uranium mill tailings impoundment discussed above, in order to receive approval for the cover and naturally attenuate reclamation plan, the license applicant needs to show to the regulatory agency that natural attenuation can effectively reduce the contaminant concentration levels so that the licensed groundwater constituents will not exceed regulatory levels at the point of compliance. 

In our opinion, the isolation of significantly different structures at such a low molecular weight is confirming evidence for the true complexity of petroleum, the need for predictive characterization techniques, and the need for extreme caution in interpreting data from any one particular analytical method (e.g., GLC, MS). 

Figure 17.1 A schematic representation of the problem of lack of data for chemicals in the environment and the need for predictive methods.

In connection with the regulatory reform in 1985, it was resolved to take care of the need for predictability by converting earlier detailed regulations to non-mandatory guidelines. This also ensured that experience gained from following up activities, and... 

In spite of considerable development of thermodynamics and molecular theory, most of the methods used today are empirical and their operation requires knowledge of experimental values. However, the rate of accumulation of experimental data seems to be slowing down even though the need for precise values is on the rise. It is then necessary to rely on methods said to be predictive and which are only estimates. 

Several research groups have built models using theoretical desaiptors calculated only from the molecular structure. This approach has been proven to be particularly successful for the prediction of solubility without the need for descriptors of experimental data. Thus, it is also suitable for virtual data screening and library design. The descriptors include 2D (two-dimensional, or topological) descriptors, and 3D (three-dimensional, or geometric) descriptors, as well as electronic descriptors. 

Because the energy production and storage 2one is far underground, HDR plants should occupy only a minimal space on the surface. In addition, siting opportunities are predicted to be extremely versatile, and the locations of faciHties can be chosen for minimal visual impact or to eliminate the need for long mns of high tension lines. 

Predictions in the 1960s of the growth in nuclear power indicated the need for recycling (qv) of nuclear fuels. RadionucHdes involved are uranium-235, uranium-238 [24678-82-8] and plutonium-239. This last is produced by neutron absorption in the reactions ... 

Process Hazards Analysis. Analysis of processes for unrecogni2ed or inadequately controUed ha2ards (see Hazard analysis and risk assessment) is required by OSHA (36). The principal methods of analysis, in an approximate ascending order of intensity, are what-if checklist failure modes and effects ha2ard and operabiHty (HAZOP) and fault-tree analysis. Other complementary methods include human error prediction and cost/benefit analysis. The HAZOP method is the most popular as of 1995 because it can be used to identify ha2ards, pinpoint their causes and consequences, and disclose the need for protective systems. Fault-tree analysis is the method to be used if a quantitative evaluation of operational safety is needed to justify the implementation of process improvements. 

As computing capabiUty has improved, the need for automated methods of determining connectivity indexes, as well as group compositions and other stmctural parameters, for existing databases of chemical species has increased in importance. New naming techniques, such as SMILES, have been proposed which can be easily translated to these indexes and parameters by computer algorithms. Discussions of the more recent work in this area are available (281,282). SMILES has been used to input Contaminant stmctures into an expert system for aquatic toxicity prediction by generating LSER parameter values (243,258). 

Enantioselective processes involving chiral catalysts or reagents can provide sufficient spatial bias and transition state organization to obviate the need for control by substrate stereochemistry. Since such reactions do not require substrate spatial control, the corresponding transforms are easier to apply antithetically. The stereochemical information in the retron is used to determine which of the enantiomeric catalysts or reagents are appropriate and the transform is finally evaluated for chemical feasibility. Of course, such transforms are powerful because of their predictability and effectiveness in removing stereocenters from a target. 

The need to predict mutual diffusion coefficients from self-diffusion coefficients often arises, and many efforts have been made to understand and predict mutual diffusion data, through approaches such as, for example, the following extension of the Darken equation [5j ... 

Vibration analysis, a key predictive maintenance tool, can be used to determine whether or not the repairs corrected existing problems and/or created addition abnormal behavior before the system is re-started. This eliminates the need for the second outage that many times is required to correct improper or incomplete repairs. 

The addition of predictive maintenance techniques as an outage-scheduling tool reduced the outage to five days and resulted in a total savings of 200,000. The predictive maintenance data eliminated the need for many of the repairs that would normally have been included in the maintenance outage. Based on the ball mill s actual condition, these repairs were not needed. The additional ability to schedule the required repairs, gather required tools and plan the work reduced the time required from three weeks to five days. 

Recent advancements in microprocessor technology coupled with the expertise of companies that specialize in machinery diagnostics and analysis technology, have evolved the means to provide vibration-based predictive maintenance that can be cost-effectively used in most manufacturing and process applications. These microprocessor-based systems simplify data acquisition, automate data management, and minimize the need for... 

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