Daan W Huntjens, Olivier J M Béquignon, Stefanie D Krens, Mark Löwenberg, Martine E D Chamuleau, Remco J Molenaar, Anita M G Kramers, Marianne A Kuijvenhoven, Imke H Bartelink
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引用次数: 0
Abstract
Aims: The study aims to predict and improve the absorption of tyrosine kinase inhibitors (TKIs) in patients with malabsorption issues, particularly those who have undergone bariatric surgery or are using proton-pump inhibitors. The research involves 2 main components: the development of an artificial intelligence (AI) model to identify TKIs that are susceptible to reduced absorption in these patients, and the application of case-specific absorption enhancements based on 2 clinical scenarios.
Methods: A fully connected neural network was applied using pH-dependent solubility data from 137 785 compounds to identify TKIs at risk of reduced bioavailability when bypassing the stomach. The clinical impact of gastric acid suppressants on the bioavailability of 71 approved TKIs was evaluated by correlating the AI solubility estimates with the effect of proton-pump inhibitors on clinical exposure. Furthermore, absorption enhancement was applied in 2 clinical scenarios, with therapeutic drug monitoring assessing the effectiveness of the enhancement.
Results: Two AI models were developed to predict the difference in molecular aqueous solubility between acid and neutral pH and to capture the concentration available for intestinal absorption in healthy and in patients with malabsorption issues. The AI model capturing the solubility difference between acidic and neutral pH demonstrated predictive capabilities, with a Pearson correlation coefficient of .95 and a coefficient of determination of .90. It predicted that the solubility difference, between acidic and neutral pH, was associated with clinical bioavailability (P < .001). Nilotinib, lapatinib and dacomitinib were ranked as TKIs with the highest risk of malabsorption in case of increased stomach pH.
Conclusion: We developed an AI-based model that predicts TKIs that are at risk of malabsorption when bypassing the stomach or used with gastric acid suppressants. Drugs with a high malabsorption risk can be enhanced by various methods to improve bioavailability.
期刊介绍：
Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.
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