Journal of Bioequivalence & Bioavailability

Prediction of in-vivo permeability, solubility, BCS-classing, food interactions, fraction absorbed and oral bioavailability using new in-silico methods and algorithms

6^th World Congress on Bioavailability & Bioequivalence: BA/BE Studies Summit

August 17-19, 2015 Chicago, USA

Urban Fagerholm and Sven Hellberg

Scientific Tracks Abstracts: J Bioequiv Availab

Abstract:

Background: Prediction of in-vivo permeability (Pe), solubility, BCS-classing, food interactions, fraction absorbed (fa) and oral
bioavailability(F) from in-vitro and animal data is a challenge, especially for compounds with low/moderate Pe, efflux and/or high
lipophilicity/low solubility. For such compounds, in-vivo prediction from preclinical data is generally poor/uncertain and sometimes
impossible. Thus, improvements are required.
Methods: With extensive, diverse datasets (log P -9 to 9), new algorithms and various computational chemistry methods (including
machine learning) we have developed and validated prospective in-silico prediction models (no retrospective data fitting) for the
parameters described above.
Results & Discussion: Models for fa and F (including compounds with low Pe, strong efflux, very low solubility, extensive gutwall
and hepatic extraction) showedQ^2 of 0.77 and 0.55 and median prediction errors of 1.1- and 1.4-fold, respectively. In direct
comparison, the models outperformed lab methods. For the 100 compounds with lowest solubility (including albendazole, danazol,
loperamide, lovastatin, ketoconazole and troglitazone), 74% correct in-vivo BCS-classing and 12% average absolute prediction error
for fa was obtained. The mean prediction error for AUC-changes with food was 1.4-fold.
Conclusion: The new in-silico models and algorithms enable improved and simplified prospective predictions of in-vivo Pe, fa,
solubility, BCS-classing, food interactions and F. Benefits include reduced and defined uncertainty, reduced time and costs, and
frontloaded and improved decision-making.

Biography :

He completed his PhD in pharmacokinetics/biopharmaceutics in Uppsala university in1997. He worked as a Senior research scientist and principle scientist at AstraZeneca
Sodertalje (1997-2012). Presently he is a CEO, founder and method developer at PROSILICO.