Determining Properties that Drive eD2M Predictions for a Series

Determining Properties that Drive eD2M Predictions for a Series 

As stated earlier, eD2M can be used both to flag compounds as potential CDs and to point to the DMPK properties that need to be optimized clearly, the first of these aspirations is a key activity in a project at the lead optimization stage, while the latter is a requirement for projects in both the H2L and LO stages. To 

Clinical dose needed to match eD2M Free Cmax (mg) 

On the face of it, when fhalf of this compound is predicted to be 3 h, it is likely to be a CD (as its dose will be 70 mg). However, the predicted Thaif only has to decrease to about 2 h for the predicted dose to become unacceptably large ( 500 mg), whereas if Thaif=6h, the predicted dose remains acceptable with a twofold reduction to 3 h. It looks like Thaif is indeed a parameter that can profoundly affect dose predictions, but is not in itself able to be optimized. However, closer inspection of the model shows that Thaif is a composite parameter  

Clearance can be predicted from in vitro data as described above, while on occasion both clearance and V ss can be driven by the unbound fraction of a drug in plasma. Consequentiy, Thaif can be optimized by focusing on CLjnt as measured in human hepatocyte or human liver microsome preparations and either 

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