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Advances in Predictions of Oral Bioavailability of Candidate Drugs in Man with New Machine Learning Methodology
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- Fagerholm, Urban (author)
- Prosilico AB, Lännavägen 7, SE-14145 Huddinge, Sweden
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- Hellberg, Sven (author)
- Prosilico AB, Lännavägen 7, SE-14145 Huddinge, Sweden
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- Spjuth, Ola, Professor, 1977- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab,Prosilico AB, Lännavägen 7, SE-14145 Huddinge, Sweden
- (creator_code:org_t)
- 2021-04-28
- 2021
- English.
- In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 26:9
- Journal article (peer-reviewed)
Abstract
Subject headings
Close
- Oral bioavailability (F) is an essential determinant for the systemic exposure and dosing regimens of drug candidates. F is determined by numerous processes, and computational predictions of human estimates have so far shown limited results. We describe a new methodology where F in humans is predicted directly from chemical structure using an integrated strategy combining 9 machine learning models, 3 sets of structural alerts, and 2 physiologically-based pharmacokinetic models. We evaluate the model on a benchmark dataset consisting of 184 compounds, obtaining a predictive accuracy (Q2) of 0.50, which is successful according to a pharmaceutical industry proposal. Twenty-seven compounds were found (beforehand) to be outside the main applicability domain for the model. We compare our results with interspecies correlations (rat, mouse and dog vs. human) using the same dataset, where animal vs. human-correlations (R2) were found to be 0.21 to 0.40 and maximum prediction errors were smaller than maximum interspecies differences. We conclude that our method has sufficient predictive accuracy to be practically useful with applications in human exposure and dose predictions, compound optimization and decision making, with potential to rationalize drug discovery and development and decrease failures and overexposures in early clinical trials with candidate drugs.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- absorption
- ADME
- bioavailability
- computational
- in silico
- PBPK
- pharmacokinetics
- prediction
- QSAR
Publication and Content Type
- ref (subject category)
- art (subject category)
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