Predicting the Influence of Fat Food Intake on the Absorption and Systemic Exposure of Small Drugs using ANDROMEDA by Prosilico Software
Fagerholm U, Hellberg S, Alvarsson J, Spjuth O.
Predicting the Influence of Fat Food Intake on the Absorption and Systemic Exposure of Small Drugs using ANDROMEDA by Prosilico Software.
bioRxiv. 2022.12.05.519072 (2022). DOI: 10.1101/2022.12.05.519072
The ANDROMEDA software by Prosilico has previously been successfully applied and validated for predictions of absorption characteristics of small drugs in man. The influence of fat food on the gastrointestinal uptake and systemic exposure of drugs have, however, not yet been evaluated with the software. The main objective was to use ANDROMEDA to predict area under the plasma concentration-time curve ratios in the fed (fat food) and fasted states (AUCfed/AUCfast) for small drugs (including those marketed in 2021) and compare results with corresponding measured clinical estimates. Actual dose sizes were considered. Another objective was to compare the performance of ANDROMEDA vs physiologically based pharmacokinetic (PBPK) modelling and simulations by The Food Effect PBPK IQ Working Group. PBPK results generated using Simcyp and GastroPlus software were based on various physicochemical, in vitro and in vivo data and a decision tree for model verification and optimization. 63 drugs, including 17 new drugs, with observed AUCfed/AUCfast between 0.2 and 5.5 were found and used for this evaluation. Predicted AUCfed/AUCfast had mean and maximum errors of 1.5- and 4.1-fold, respectively, and the predictive accuracy (correlation between predicted and observed AUCfed/AUCfast; Q2) was 0.3. 14 % of predictions had >2-fold error. For 72 % of drugs, food interaction class was correctly predicted. The level of predictive accuracy was overall similar to results obtained with PBPK modelling and simulations, however, with lower maximum error and higher compound coverage. With PBPK models, maximum simulation error was 7.7-fold and 3 highly lipophilic compounds were not possible to simulate. The results validate ANDROMEDA for prediction of fat food-drug interaction size for small drugs in man. Major advantages with the methodology include that prediction results are produced directly from molecular structure and oral dose and are similar to PBPK-simulation results obtained using in vitro and clinical data. Furthermore, ANDROMEDA showed lower maximum errors and wider compound range.