ANDROMEDA by Prosilico Software Successfully Predicts Human Clinical Pharmacokinetics of 300 Drugs Out of Reach for In Vitro Methods

Abstract

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIntroductionC_ST_ABSIn vitro measurements and predictions of human clinical pharmacokinetics (PK) are sometimes hindered and made impossible due to factors such as extensive binding to materials, low methodological sensitivity and large variability. MethodsThe objective was to find compounds out of reach for in vitro PK-methods and (if possible) predict corresponding human clinical estimates using the ANDROMEDA by Prosilico software. In vitro methods selected for the investigation were human microsomes and hepatocytes for measuring and predicting intrinsic hepatic metabolic clearance (CLint), Caco-2 and Ralph Russ canine kidney cells (RRCK) cells for measuring apparent intestinal permeability (Papp) for prediction of fraction absorbed (fa), plasma for measurement and estimation of unbound fraction (fu), and water and buffers for measuring solubility (S) for prediction of in vivo dissolution potential (fdiss). Results and ConclusionAs many as 329 non-quantifiable in vitro PK-measurements for 300 compounds were found in the literature: 191 for CLint, 101 for Papp, 11 for fu and 26 for S. ANDROMEDA was successful in predicting all corresponding clinical PK-estimates for the selection of compounds with non-quantifiable in vitro PK, and predicted estimates (1.6-fold median prediction error; n=159) were generally in line with observed in vivo data and results/problems at in vitro laboratories. Thus, ANDROMEDA is applicable for predicting human clinical PK for compounds out of reach for laboratory methods.