Comparing Lipinskis Rule of 5 and Machine Learning Based Prediction of Fraction Absorbed for Assessing Oral Absorption in Humans

Abstract

Background - The influential Lipinskis Rule of 5 (Ro5) describes molecular properties important for oral absorption in humans. According to Ro5, poor absorption is more likely when 2 or more of its criteria (molecular weight (MW) above 500 g/mol, calculated octanol-water partition coefficient (clog P) above 5, above 5 hydrogen bond donors (HBD) and above 10 hydrogen bond acceptors (HBA)) are violated. Earlier evaluations have shown that many drugs are sufficiently well absorbed into the systemic circulation despite many Ro5-violations. No evaluation of Ro5 vs fraction absorbed (fa) has, however, been done. Methods - Datasets of orally administered drugs violating and not violating Ro5 and with available human clinical fa-values were assembled, and contrasted to machine learning based predictions using the ANDROMEDA prediction software having a major MW-domain of 150-750 g/mol. Results - 129 Ro5-violent compounds (29 with MW above 1000 g/mol) were found, 59 of which had fa-values (42 % mean fa). 34 % and 66 % of compounds were predicted as having fa below 10 % and above 10-30 % respectively, which was in good agreement with measured fa of 37 % and 63 %. The fa for all compounds with fa above 5 % and above 10 % were correctly predicted. For compounds with fa above 30 %, 81 % were predicted to have a fa above 30 %, but none were predicted to have a fa below 10 %. The Q2 for predicted vs observed fa was 0.64. For a set of 77 compounds without Ro5 violation (80 % mean fa), all compounds were correctly predicted to have a fa below or above 30 % (Q2=0.56). Among these are compounds with poor uptake (below 1 % to 7 %). Conclusion - We show that machine learning based predictions of fa are superior to Ro5 for assessing oral absorption obstacles in humans. Too strict reliance on Ro5 may hence constitute a risk. ANDROMEDA predicts fa well, easily and quickly, and also differentiates well between poor and adequate oral uptake for compounds violating and not-violating Ro5. This makes it a valid and useful tool capable of predicting oral absorption in humans with good accuracy and replacing Ro5 for oral absorption assessments.