Abstract
Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73−14.27)), together with age (1.05 (1.02−1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing.
Highlights
Adverse drug reactions (ADRs) are common phenomena that impact our health system
All genotyped markers included in the iPLEX® PGx 74 Panel to derive the metabolic profiles of the genes CYP2C9 (#10 markers), CYP2C19 (#8), VKORC1 (#1) were in a Hardy–Weinberg Equilibrium (HWE)
The PGx effect on the ADR cases was prominent at higher activity of CYP2C19, presenting with an ADR that was caused by the CYP2C19 substrate clopidogrel, but anticoagulant activity determined by the pharmacogenomics risk profiles of CYP2C9 combined with VKORC1 showed an impact on the phenprocoumon-suspecting ADRs
Summary
Adverse drug reactions (ADRs) are common phenomena that impact our health system. Around 6.5% of all consultations in the hospital emergency department (ED) are caused by serious ADRs [1,2,3] that mainly affect older, multi-medicated patients [4]. PGx was described to smoothen the way for personalized medicine, improving the efficacy and safety of drug treatment [7], as well as offering a probable cost-effective solution by preventing serious ADRs [8]. In systematic reviews, those drugs that commonly cause ADRs are shown to be metabolized by polymorphic enzymes [9], which might have a clinical impact on required dosages. Individuals might be overdosed with standard drug dosages, potentially leading to ADRs. Often affected is the metabolism of drugs acting on the central nervous system, such as antidepressants or antipsychotics. A lack of clinical trials that aim to demonstrate the advantages associated with pharmacogenomic testing was often pointed out [12]
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