20.500.12556/DiRROS-29737 Higher incidence of common polymorphisms in the genes of folate and methionine cycles in children with orofacial clefs and congenital heart defects compared to their unaffected siblings Background: Bioequivalence risk assessment as an extension of quality risk management lacks examples of quantitative approaches to risk assessment at an early stage of generic drug development. The aim of our study was to develop a model-based approach for bioequivalence risk assessment that uses pharmacokinetic and physicochemical characteristics of drugs as predictors and would standardize the first step of risk assessment. Methods: The Sandoz in-house bioequivalence database of 128 bioequivalence studies with poorly soluble drugs (23.5% non-bioequivalent) was used to train and validate the model. Four different modeling approaches, random forest, XGBoost, logistic regression and naïve Bayes, were compared. Results: Among the best performing machine learning models, random forest was selected and optimized for the number of features, resulting in an accuracy of 84% on the test data set. The most important features for prediction were those related to solubility (dose number, acid dissociation constant), absorption and elimination rate, effective permeability, variability of pharmacokinetic endpoints, and absolute bioavailability. All features had a conceivable influence on the model predictions. Conclusion: The model was used to develop a bioequivalence risk assessment approach to categorize drugs in early development into high, medium or low risk classes. congenital heart disease folate metabolism FPGS genetics orofacial clefts polymorphisms sibling pairs prirojena srčna napaka metabolizem folatov FPGS orofacialne razjede polimorfizmi bratje in sestre pari true false true Angleški jezik Slovenski jezik Neznano 2026-06-04 10:35:24 2026-06-04 10:35:25 2026-06-05 04:05:56 0000-00-00 00:00:00 2024 0 0 Št. članka: e2408; 11 str. iss. 11 Vol. 116 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 575:616.12-039 2472-1727 10.1002/bdr2.2408 213546755 RAZ_Karas_Kuzelicki_Natasa_2024.pdf RAZ_Karas_Kuzelicki_Natasa_2024.pdf 1 ED451CA1260907925914A2231AEF16E6 d14a91462b0a9911728f33da3d54730bdf5c601804c631a8f27908c8fb687952 759d5800-5ff0-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=44688 https://onlinelibrary.wiley.com/doi/10.1002/bdr2.2408 1 56cc0b01-5ff0-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=44687 Univerzitetni klinični center Ljubljana 0 0 0