In silico predictions of the gastrointestinal uptake of macrocycles in man using conformal prediction methodology
Fagerholm U, Hellberg S, Alvarsson J, and Spjuth O..
In silico predictions of the gastrointestinal uptake of macrocycles in man using conformal prediction methodology.
Journal of Pharmaceutical Sciences. In press (2022). DOI: 10.1016/j.xphs.2022.05.010
The gastrointestinal uptake of macrocyclic compounds is not fully understood. Here we applied our previously validated integrated system based on machine learning and conformal prediction to predict the passive fraction absorbed (fa), maximum fraction dissolved (fdiss), substrate specificities for major efflux transporters and total fraction absorbed (fa,tot) for a selected set of designed macrocyclic compounds (n=37; MW 407-889 g/mol) and macrocyclic drugs (n=16; MW 734-1203 g/mole) in vivo in man. Major aims were to increase the understanding of oral absorption of macrocycles and further validate our methodology. We predicted designed macrocycles to have high fa and low to high fdiss and fa,tot, and average estimates were higher than for the larger macrocyclic drugs. With few exceptions, compounds were predicted to be effluxed and well absorbed. A 2-fold median prediction error for fa,tot was achieved for macrocycles (validation set). Advantages with our methodology include that it enables predictions for macrocycles with low permeability, Caco-2 recovery and solubility (BCS IV), and provides prediction intervals and guides optimization of absorption. The understanding of oral absorption of macrocycles was increased and the methodology was validated for prediction of the uptake of macrocycles in man.