Drug-drug-gene interactions and adverse effects on the immunosystem
Professor, Institute of Clinical Pharmacology, University Hospital of RWTH University Aachen, Germany
Introduction: Adverse drug reactions (ADRs) and medication errors are a relevant problem in the context of health. Estimates approximately 5%-15% of emergency hospitalizations are due to ADRs. Many ADR affect the immunosystem and our body’s defense system against infections.
Methods: The basis for this evaluation was the recording of suspected cases of ADR in patients who came to the hospital emergency department in four large hospitals in Germany. We analysed drug interactions together with pharmacogenetic profiles in this cohort study on adverse drug reactions leading to emergency visits (ADRED study with n=2939 cases). Suspected cases of ADR were documented if considered "possible", "probable", or "certain" according to WHO-UMC criteria for associations with drug therapy. A biosample for pharmacogenetic analyses was taken if patients had provided informed consent.
Results: In the participating emergency departments, 6.5% of all treatment cases were detected as suspected ADRs during the observation period of the feasibility analysis. The majority of the study cases collected involved patients who were, older (median: 73 years) and multimorbid (72.4%). Accordingly, most of the cases are also polymedicated (median: 7 drugs). Pharmacogenetic analyses were done in n=776 of the total sample of n=2215. It turned out that drugs affected by pharmacogenetic polymorphisms were more frequently suspected being causative for the ADR in patients who turned out to be pharmacogenetic risk allele carriers in the pharmacogenetic analyses done retrospectively.
Equal pathways of drug metabolism mediated drug drug interactions with the number of substrates and inhibitors of the same CYP enzyme pathway correlating with adverse drug reactions. The adverse effect dizziness was associated with the number of concomitantly taken CYP2D6 substrates and inhibitors, indicating a drug-drug interaction effect on the CYP2D6 phenotype. However, the number of subjects genotyped in this cohort was too low to show additional gene-drug-drug interactions. For CYP2C19, and CYP2C9, risk genotypes were associated with bleeding in polytherapy-patients.
Conclusions: Drug drug interactions in polymedication and pharmacogenetics are potential risk factors for adverse drug effects modulating our immune defence. The assessment of drug-drug-gene interactions may be based on larger datasets and more sophisticated methods like random modelling approaches and the integration of drug interaction knowledge graphs.
Acknowledgements: The study was funded by the German Ministery of Health by a grant to J. Stingl during the years 2016-2022