In vitro ADME

A lead is variously defined in the pharmaceutical industry as a compound derived from a hit with some degree of in vitro optimization (potency in primary assay, activity in functional and/or cellular assay), optimization of physical properties (solubility, permeability), and optimization of in vitro ADME properties (microsomal stability, CYP inhibition). Moreover, a lead must have established SAR/SPR around these parameters such that continued optimization appears possible. A lead may also have preliminary PK and in vivo animal model data. However, it is the task of the lead optimization chemist to improve PK and in vivo activity to the levels needed for identification of a clinical candidate. 

Included in this table are criteria related to kinase inhibition, including detailed analyses of reversibility, detergent effects, and competition with ATP. Also listed are criteria for selectivity, cellular activity, and the physicochemical and in vitro ADME profiles. The final two criteria require the lead to be part of a series of compounds with demonstrated SAR. 

Chemical Leads Primary Assay IC50 < 1 pM Selectivity Assay 10-fold selectivity Cellular Assay IC50< 1 pM Acceptable in vitro ADME Acceptable PK Profile Potentially patentable... 

Drug candidates that are intended for oral dosing need to have good ADME properties so that they can be dosed once or twice daily. The drug should be well absorbed, survive first pass metabolism, and have sufficiently low clearance. At the lead identification stage, the primary in vitro ADME assays employed are those that assess permeability and metabolic stability. There are a variety of assays available for both parameters, as described in the previous chapter. 

It is also important to correlate PK data with in vitro ADME assay data for each series to validate the predictive potential for the in vitro assays within a series. Once this is done, one can rely on the in vitro assays with more confidence. 

Some in vitro ADME and safety assays (e.g., microsomal stability and hERG blockade) may not be possible with poorly soluble compounds. 

Kassel, D. B. High throughput strategies for in vitro ADME assays how fast can we go in Using Mass Spectrometry for Drug Metabolism Studies, CRC Press, Boca Raton, 2005. 

In vitro ADME profile assay selection and profile... 

Neighbor-based ADME interpretation can also be performed using the in vitro ADME subset of the BioPrint profile. Just as the pharmacological profile of a new compound is used to look for compounds with similar pharmacological profiles, the ADME profile can be used to identify compounds with similar ADME profiles. 

Figure 8. Heat map of a cluster of BioPrint compounds with similar in vitro ADME profiles. Eight ADME assays are clustered on the X-axis and 8 compounds are clustered on the Y-axis. Normalized data range from 0 (blue-green) to 2 (red). Clustering is performed using Pearson correlation and complete linkage using normalized dataset. Where available in literature, human in vivo oral absorption (oa) and oral bioavailability (ba) values (%) are presented after the compound name.

Figure 8 shows a cluster of BioPrint compounds with similar ADME profiles. All the compounds in this cluster share the pharmacokinetic properties of having near total oral absorption and oral bioavailability. Thus, we have identified an in vitro ADME profile that appears to be highly predictive of good absorption and bioavailability properties. 

In Vitro Target In Vitro ADME Physical Properties In Vivo Safety... 

Early Access to physicochemical and in vitro ADME Data... 

Wu X, Wang J, Tan L et al (2012) In vitro ADME profiling using high-throughput rapid-fire mass spectrometry cytochrome p450 inhibition and metabolic stability assays. J Biomol Screen 17 761-772... 

Exploration of available chemical space Advanced medicinal chemistry approaches Broader selectivity studies Detailed pharmacophore analysis Results from in vitro ADME/T studies PK and PD characteristics... 

Preliminary in vitro ADME/T profiling. In vitro ADME/T and physicochemical profiling assays are routinely employed to optimize the drug-like properties of analogues and to aid in the selection of compounds for further development see Table 4 for ideal metrics). 

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