Attrition due to lack of efficacy in clinical trials continues to be a problem in drug discovery and development. Piecemeal rules of thumb such as those that make up Lipinski’s Rule of Five have helped identify candidates that are liable to fail due to solubility and absorption problems, there are many combinations of properties that can also lead to development failure. The best way to identify these are the full-scale physiologically-based pharmacokinetic (PBPK) simulations available in programs like GastroPlus™. Such programs are designed primarily to analyze pre-clinical or clinical trial data on individual subjects, and so have to be configurable to take variations in subject sex, weight, and disease state into account. For optimal performance, they also need to know details about transporters and metabolic details that are rarely available early in a project. Such details are much less relevant in discovery and lead optimization, where the important thing is to anticipate generic problems with a class of chemistry and to differentiate such problems from ones that are specific to one or a few examples from a class. We have created a simplified and streamlined version of the GastroPlus gastrointestinal absorption (ACAT™) that runs as a Simulation Module within ADMET Predictor™, enabling users to easily estimate fraction absorbed (Fa) and fraction available after first-pass metabolism (Fb) for thousands of compounds for typical rat or human subjects. Experimental values for solubility and in vitro metabolism can be used if available, but reasonable results are obtained from purely in silico property predictions in many cases. Moreover, deviations from those predictions can provide important insight into complicating factors – e.g., precipitation, transporters or non-CYP metabolism – that are best addressed early in development.

High-throughput prediction of fraction absorbed and bioavailability in silico

255th National Meeting (2018)

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