ADME/Tox testing

While utilizing the HTS expertise and capacity might deliver the initial desired results, we recommend that serious considerations are given to the transfer of expertise and build up of a local automation and support infrastructure that is specific to the needs of ADME/Tox testing in order to understand crucial process steps, vhen a rapid scale up is required. 

Combination of Potency Screening with Early ADME/Tox Testing... 

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

Sugano, H. Artifidal membrane technologies to assess transfer and permeation of drugs in drug discovery. In ADME/Tox Approaches, Tests, B.,... 

More recently, another linear discriminant analysis (LDA) model was constructed for a set of 157 compounds for which Pcaco-2 was measured [43]. This model, which applied DRAGON descriptors, achieved an accuracy of classification at 91 % for the training set and 84% for the test set. When this model was applied to predict a set of 241 drugs for which HIA data were available, good correlation (>81%) was achieved between the two ADME-Tox properties. 

Requests typically come from the lead optimization group for a set of compounds to be tested in a number of ADME/Tox assays. These could be according to predefined campaign strategy or selected a la carte. 

Ideally the ADME/Tox screening laboratory service vould be set up to fiexibly offer choice in the screening strategy that best fits the current campaign circumstances. It vould also provide real-time data feedback both to enable researchers to use the critical information to make decisions on further testing and to reduce cycle times by eliminating compounds midcampaign [6]. 

Materials in the ADME/Tox screening process relate mainly to consumables (plastic ware, tips, plates, reagents, etc.) and the raw materials the tests will be performed on, which are plates with compounds and cells. To simplify the analysis, it is assumed that access to consumables is not a major issue, since these supplies can easily be ordered through the supply chain and are generally available to the personnel performing the test assays (Figures 1.4 to 1.7). 

St. Jude Children s Research Hospital Supplemental data from Guiguemde et al. (25) structures tested in a primary screen, with additional data in 8 protocols Bland-Altman analysis, calculated ADME-tox properties, phylochemogenetic screen, sensitivity, synergy, and enzyme assays, as well as a thermal melt analysis. 1,524... 

Antimalarial ADME/tox assays in vitro in vivo testing, hit L identification A r Virtual screening- Predict antimalarial actives, ADME/tox t properties A... 

Fig. 3 Diagramatic representation of Old and New strategies for lead optimization of new pharmaceutical molecules. The top section indicates the Old (and in some cases, current) way in which pharmaceutical companies take Hits to lead development candidate through discovery and early preclinical development testing. Essentially, no high-throughput formal lead optimization exists in this model but is developed for backup compounds by using biomarkers identified during lead compound failure in vivo. The bottom section indicates the New way forward (used now by most major pharmaceutical companies). In this model, a formal in vitro PLOT battery is inserted early in development before preliminary in vivo ADME-Tox screening and subsequent lead development candidate selection.

Fig. 3.1 Stairway to drug discovery. The drug discovery process as modeled here is not necessarily a linear process. Novel potential biopharmaceuticals (e.g., siRNAs) used in early steps of target identification and validation can, in principle, skip the next steps and be tested directly in ADME/tox-icity studies (see Part VI11, Chapter 4). ADM E, Adsorption, Distribution, Metabolism, and Excretion HTS, high-throughput screening.

---