engleski

Pharmacogenomics in the prediction of cardiovascular drugs adverse reactions - PGx-CardioDrug

Objective: To investigate the multiple drug-drug- gene interactions and their relevance for predicting cardiovascular drugs' adverse drug reactions (ADRs). Preliminary data from our prospective nested case-control study are presented. Patients and methods: The primary cohort of cardiovascular disease patients is represented by subjects who have a new indication for the administration of direct oral anticoagulants (DOAC: dabigatran etexilate, apixaban, rivaroxaban, edoxaban) ; platelet aggregation inhibitors (PAI: clopidogrel, prasugrel, ticagrelor), HMG-CoA reductase inhibitors (simvastatin, atorvastatin, rosuvastatin). Patients were enrolled during the 16 months. The cases represent subjects that developed ADRs during the follow-up period: bleeding from DOACs and PAIs, myotoxicity and hepatotoxicity from statins, other serious ADRs. Control subjects are recruited from the same cohort, among subjects with no ADRs from the enrolment to at least 3- month follow up. All subjects were genotyped for relevant ADME gene variants: CYP2C9 *2*3, CYP2C19 *2*3*17, CYP2D6 *3*4*5*6*9*10*41 and xN, CYP2J2*7, CES1 (rs2244613, rs8192935), ABCB1 (c.1236C>T, c.2677G>T/A, c.3435C>T, rs4148738), ABCG2 c.421C>A, SLCO1B1 c.521T>C by Real-Time PCR methods, depending on the used therapy, and were monitored for clinical and laboratory parameters. For drug-drug interactions (DDI), The Lexicomp® Clinical Decision Support System was applied. Results: 450 patients were recruited (female=215, male=235). Among them were genotyped according to prescribed drug substrates for CYP2C9 (n=211 ; 47%), CYP2C19 (n=262 ; 58%), CYP3A4 (n=335, 74%), CYP3A5 (n=299, 66%), CYP2D6 (n=101, 22%), CES1 (n=32, 7%), ABCB1 (n=282, 63%), ABCG2 (n=357, 79%), SLCO1B1 (n=214, 48%). ADRs observed were: myotoxicity (n=84, 17%), hepatotoxicity (n=14, 3%), bleeding (n=36, 9%). Potential DDI with increased risk for ADRs were found in group of statins (n=39/182 ; DDI level C=28/182, 15% ; level D=4/182, 2%), DOACs (n=133/135, DDI level C=21%, D=26%) and PAIs (n=68/76, DDI level C=71%, D=2.6%). Conclusion: Our preliminary data point to the drug-drug-gene interactions as an important risk factor for cardiovascular drug adverse reactions.

drug safety ; interactions ; multidisciplinary ; pharmacogenetic ; risk factors ; cardiovascular drugs

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