Predicting Gastrointestinal Absorption of Prodrugs and their Drugs with the ANDROMEDA by Prosilico Software

Abstract

AbstractIntroductionSome prodrugs are developed in order to improve gastrointestinal absorption properties such as permeability and solubility/dissolution. Prediction of the uptake of prodrugs and their drugs is challening for reasons including gastrointestinal hydrolysis and active transport.Objective and MethodologyThe objective was to use the ANDROMEDA software by Prosilico to predict absorption characteristics - passive fraction absorbed (fa,passive), dose-adjusted dissolution potential (fdiss) and total fa(fa) - of prodrugs and their drugs (including drugs and their active metabolites), and to evaluate how they differ between prodrugs and drugs and the predictive accuracy of the software.Results70 prodrug-drug pairs were found and selected for the study. The mean predicted fa,passiveand fdissfor the prodrugs were 0.74 and 0.94, respectively. Corresponding estimates for the drugs were 0.72 and 0.98, respectively. For non-hydrolyzed prodrugs, the median relative and absolute prediction errors for fawere 1.17-fold and 0.08, respectively. Corresponding values for drugs were 1.11-fold and 0.07, respectively. The correlation between predicted and observed fafor non-hydrolyzed ester prodrugs and drugs combined (predictive accuracy) was 0.6.ConclusionProdrugs and drugs had similar average predicted fa,passiveand fdiss, and most had or were predicted to have at least 50 % fa. The fafor about 1/3 of non-hydrolyzed prodrugs was higher than for corresponding drugs, showing successful prodrug design. Adequate prediction accuracy validates ANDROMEDA for prediction of prodrug and drug absorption in man.