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Item Comparative analysis of chemical descriptors by machine learning reveals atomistic insights into solute–lipid interactions(ACS American Chemical Society, 2024-05-23) Lange, Justus Johann; Anelli, Andrea; Alsenz, Jochem; Kuentz, Martin; O'Dwyer, Patrick J.; Saal, Wiebke; Wyttenbach, Nicole; Griffin, Brendan T.; H2020 Marie Skłodowska-Curie Actions; Horizon 2020This study explores the research area of drug solubility in lipid excipients, an area persistently complex despite recent advancements in understanding and predicting solubility based on molecular structure. To this end, this research investigated novel descriptor sets, employing machine learning techniques to understand the determinants governing interactions between solutes and medium-chain triglycerides (MCTs). Quantitative structure-property relationships (QSPR) were constructed on an extended solubility data set comprising 182 experimental values of structurally diverse drug molecules, including both development and marketed drugs to extract meaningful property relationships. Four classes of molecular descriptors, ranging from traditional representations to complex geometrical descriptions, were assessed and compared in terms of their predictive accuracy and interpretability. These include two-dimensional (2D) and three-dimensional (3D) descriptors, Abraham solvation parameters, extended connectivity fingerprints (ECFPs), and the smooth overlap of atomic position (SOAP) descriptor. Through testing three distinct regularized regression algorithms alongside various preprocessing schemes, the SOAP descriptor enabled the construction of a superior performing model in terms of interpretability and accuracy. Its atom-centered characteristics allowed contributions to be estimated at the atomic level, thereby enabling the ranking of prevalent molecular motifs and their influence on drug solubility in MCTs. The performance on a separate test set demonstrated high predictive accuracy (RMSE = 0.50) for 2D and 3D, SOAP, and Abraham Solvation descriptors. The model trained on ECFP4 descriptors resulted in inferior predictive accuracy. Lastly, uncertainty estimations for each model were introduced to assess their applicability domains and provide information on where the models may extrapolate in chemical space and, thus, where more data may be necessary to refine a data-driven approach to predict solubility in MCTs. Overall, the presented approaches further enable computationally informed formulation development by introducing a novel in silico approach for rational drug development and prediction of dose loading in lipids.Item Predictive computational models for assessing the impact of co-milling on drug dissolution(Elsevier, 2024-04-30) Pätzmann, Nicolas; O'Dwyer, Patrick J.; Beránek, Josef; Kuentz, Martin; Griffin, Brendan T.; HORIZON EUROPE Marie Sklodowska-Curie Actions; Horizon 2020Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.Item Developing an in vitro lipolysis model for real-time analysis of drug concentrations during digestion of lipid-based formulations(Elsevier, 2023-12-20) Ejskjær, Lotte; O'Dwyer, Patrick J.; Ryan, Callum D.; Holm, René; Kuentz, Martin; Box, Karl J.; Griffin, Brendan T.; HORIZON EUROPE Marie Sklodowska-Curie Actions; Horizon 2020Understanding the effect of digestion on oral lipid-based drug formulations is a critical step in assessing the impact of the digestive process in the intestine on intraluminal drug concentrations. The classical pH-stat in vitro lipolysis technique has traditionally been applied, however, there is a need to explore the establishment of higher throughput small-scale methods. This study explores the use of alternative lipases with the aim of selecting digestion conditions that permit in-line UV detection for the determination of real-time drug concentrations. A range of immobilised and pre-dissolved lipases were assessed for digestion of lipid-based formulations and compared to digestion with the classical source of lipase, porcine pancreatin. Palatase® 20000 L, a purified liquid lipase, displayed comparable digestion kinetics to porcine pancreatin and drug concentration determined during digestion of a fenofibrate lipid-based formulation were similar between methods. In-line UV analysis using the MicroDISS ProfilerTM demonstrated that drug concentration could be monitored during one hour of dispersion and three hours of digestion for both a medium- and long-chain lipid-based formulations with corresponding results to that obtained from the classical lipolysis method. This method offers opportunities exploring the real-time dynamic drug concentration during dispersion and digestion of lipid-based formulations in a small-scale setup avoiding artifacts as a result of extensive sample preparation.Item Hospitalisation and adverse drug events in a geriatric oncology setting: A systematic review of the literature(Elsevier Inc., 2024-05-01) Walsh, Darren J.; O'Driscoll, Michelle; Horgan, Anne M.; Tabb, Eoin; Hannan, Michelle; Morris, Colette; Sahm, Laura J.Background: Geriatric Oncology is a specialty where a multidisciplinary approach can address the unmet needs of older adults with cancer. Older adults are at increased risk of adverse drug events (ADE) due to age-related changes in pharmacokinetics and pharmacodynamics, increasing treatment complexity, and medication burden. Objectives: To review the literature to determine the incidence of unplanned hospitalisation due to ADE for all medications, both systemic anticancer therapy (SACT) and non-SACT medications. Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search included the following databases: PubMed, CINAHL, and Embase. A manual search of Scopus was then performed. Study quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions, Mixed Methods Appraisal Tool (MMAT) and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Results: Overall, three studies were included. One observational study reported 19 % of unplanned hospital admissions due to ADE in patients aged ≥70 years with cancer. The first retrospective study reported 24 % of unplanned hospital admissions are due to ADE in patients aged ≥70 years with cancer, and the second retrospective study reported 26 % of patients with metastatic melanoma treated with immune checkpoint inhibitors had an unplanned hospital admission due to an ADE. Conclusion: There is a paucity of studies assessing unplanned hospitalisation due to ADE in older adults with cancer. Future studies are needed and should account for the reporting of potential ADE relative to supportive care, ancillary medications, and indeed chronic medications used to treat long-standing comorbidities.Item Investigation of halogenated furanones as inhibitors of quorum sensing-regulated bioluminescence in Vibrio harveyi(Future Science Group, 2023-03-17) Pinheiro, Jorge; Lyons, Thérèse; Las Heras, Vanessa; Recio, Miguel Villoria; Gahan, Cormac G. M.; O'Sullivan, Timothy P.Aim: Vibrio harveyi is a Gram-negative marine bacterium that is a model system in the study of quorum sensing (QS). V. harveyi uses multichannel QS, mediated by three signaling molecules. The aim of this study was to synthesize and screen a diverse series of furanones for their potential to inhibit V. harveyi quorum sensing. Materials & methods: A library of halogenated furanones was prepared and derivatized using standard Pd-mediated coupling reactions and subsequently evaluated for their effects on V. harveyi bioluminescence. Results & conclusion: Several furanones inhibited QS-regulated bioluminescence, with gem-dichlorofuranone and tribromofuranone compounds proving especially effective. Importantly, a number of compounds were effective inhibitors of V. harveyi bioluminescence but did not have an impact on bacterial growth.