Farmakogenetika i interakcije direktnih oralnih antikoagulantnih lijekova

Direktni oralni antikoagulansi (DOAK) posljednjih su godina pokazali rastući trend propisivanja zbog povoljne farmakokinetike i farmakodinamike bez potrebe za rutinskim nadzorom koagulacije. Svoj antikoagulantni učinak ostvaruju izravnom inhibicijom trombina (dabigatran) ili izravnom inhibicijom aktiviranog čimbenika X (rivaroksaban, apiksaban i edoksaban). Iako DOAK-i stupaju u manje interakcija s drugim lijekovima u usporedbi s varfarinom, kombinacija DOAK-a i mnogih lijekova zahtijeva oprez te u nekim slučajevima i klinički nadzor. Nedavne studije dokumentirale su interindividualnu varijabilnost u razinama DOAK-a u plazmi i odgovoru pacijenta na lijek. Iako klinički i biokemijski čimbenici mogu dovesti do interindividualnih varijabilnosti prisustvo genskih varijanti ili interakcije lijekova mogu doprinijeti tim razlikama. Potrebno je razumjeti ulogu farmakogenomike prvenstveno polimorfizam gena metaboličkih enzima i prijenosnika lijekova u interindividualnoj varijabilnosti četiri najčešće propisivana DOAK-a. Cilj istraživanja: Pregledno prikazati kako farmakogenetička predispozicija, prvenstveno polimorfizmi gena CYP3A4/5 i CES1, koji kodiraju metaboličke enzime, te ABCB1 i ABCG2, koji kodiraju transportne proteine, uz interakcije lijekova u politerapiji mogu doprinijeti interindividualnoj varijabilnost razina DOAK-a u plazmi, te učinkovitosti i sigurnosti njihove primjene. Materijali i metode: Prilikom izrade ovog rada provedena je opsežna pretraga nedavno objavljenih izvornih i preglednih znanstvenih radova, kliničkih ispitivanja, in vitro studija, terapijskih smjernica i publikacija stručnih društava. Naglasak je na polimorfizmima farmakogena bitnih za farmakokinetiku DOAK-a: gena CYP3A4/5 i CES1, za enzime uključene u biotransformaciju, te gena ABCB1 i ABCG2, za transportere lijekova i njihovom doprinosu u interindividualnoj varijabilnosti i bioraspoloživosti DOAK-a, te rizicima razvoja neželjenih učinaka prvenstveno krvarenja. Pretražena je baza podataka PubMed, Web of Science, Cochrane, Google Schoolar koristeći ključne riječi: apiksaban, CES1, CYP3A4, CYP3A5, dabigatran, direktni oralni antikoagulansi, edoksaban, farmakogenetika, farmakogenomika, genske varijante, interakcije gen-lijek, interakcije lijek-lijek, 4 krvarenje, novi oralni antikoagulansi, polimorfizam gena transportera ABCB1, ABCG2, rivaroksaban, SNP, tromboembolijski događaji u razdoblju od zadnjih 10-ak godina. Prikazani su interesantni slučajevi pacijenata iz kliničke prakse koji su zbog farmakogenetičke predispozicije i interakcije lijekova razvili nuspojave DOAK-a u vidu krvarenja. Raspravljene su prisutne dileme, te predočeno trenutno stanje u Hrvatskoj uspoređeno sa situacijom u Europi i drugdje u svijetu. Rezultati: Nekoliko varijanti gena CES1 i ABCB1 se smatra potencijalno odgovornim za nastanak interindividualnih varijabilnosti DOAK-a. Utvrđeno je da su varijante gena CES1 rs2244613 i rs8192935 povezane s nižim trough koncentracijama dabigatrana i nižim rizikom od krvarenja. S druge strane varijanta gena ABCB1 rs1045642 povezuje s povećanim vršnim koncentracijama dabigatrana i rivaroksabana, te povećanom učestalošću krvarenja. Farmakogenetička analiza varijanti gena ABCB1 rs2032582 (C.2677G> T) i rs104562 (C3435C> T) mogla bi biti opravdana i od koristi kod pacijenata na terapiji rivaroksabanom. Da bi se spriječili neželjeni učinci tijekom terapije apiksabanom kod nositelja nefunkcionalnih alela gena CYP3A5 potrebano je pažljivo odabrati dozu i pratiti nuspojave. Postoji veliki rizik od razvoja neželjenih učinaka lijeka kad se edoksaban kombinira s lijekovima koji inhibiraju CYP izoenzime u homozigotnih nositelja nefunkcionalnih alela za gen CYP3A5. Zaključak: Polimorfizam gena zajedno s istovremenom primjenom inhibitora/induktora transportnih proteina ili enzima odgovornih za metabolizam lijeka može povećati rizik od nastanka štetnih događaja vezanih uz promjenu DOAK-a. Due to good pharmacokinetics and pharmacodynamics without the requirement for routine coagulation monitoring, direct oral anticoagulants (DOAK) have seen an increase in prescribing in recent years. DOAC achieves its anticoagulant effect by direct inhibition of thrombin (dabigatran) or direct inhibition of activated factor X (rivaroxaban, apixaban and edoxaban). Although DOACs interact less with other drugs compared to warfarin, the combination of DOAC and many drugs requires caution and clinical supervision in some cases. Recent studies have documented interindividual variability in DOAC plasma levels and patient response to the drug. Although clinical and biochemical factors may lead to interindividual variability, the presence of genetic variants or drug interactions may contribute to these differences. The role of pharmacogenomics, namely polymorphism of metabolic enzyme genes and drug transporters, in the interindividual variability of the four most often prescribed DOACs, must be understood. Objectives: Demonstrate how pharmacogenetic predisposition, primarily polymorphisms of CYP3A4 / 5 metabolic enzyme genes, and CES1 and ABCB1 and ABCG2 transport proteins with drug interactions in polytherapy, may contribute to interindividual variability in DOAC plasma levels, and their efficiency and safety. Materials and methods: During the preparation of this paper, an extensive search of recently published original and reviewed scientific papers, clinical trials, in vitro studies, therapeutic guidelines and publications of professional societies was conducted. The emphasis is on pharmacogen polymorphisms that are important for DOAC pharmacokinetics: CYP3A4 / 5 and CES1 genes, for enzymes involved in biotransformation, and ABCB1 and ABCG2 genes, for drug transporters and their contribution to interindividual variability and bioavailability of DOACs, effects primarily of bleeding. The database PubMed, Web of Science, Cochrane, Google Schoolar were searched using keywords: apixaban, CES1, CYP3A4, CYP3A5, dabigatran, direct oral anticoagulants, edoxaban, pharmacogenetics, pharmacogenomics, gene variants, drug-drug interactions, gene-drug interactions, bleeding, new oral anticoagulants, polymorphism of transporter genes ABCB1, ABCG2, rivaroxaban, SNP, thromboembolic events in the period of the last 10 years. Interesting cases of patients from clinical practice who have developed DOAC side effects in the form of bleeding due to pharmacogenetic predisposition and drug interactions are presented. The present dilemmas were discussed, and the current situation in Croatia was compared to the situation in Europe and elsewhere in the world. Results: Several variants of the CES1 and ABCB1 genes are thought to be potentially responsible for the occurrence of interindividual variability in DOAC. Variants of the CES1 rs2244613 and rs8192935 genes were found to be associated with lower trough out dabigatran concentrations and a lower risk of bleeding. On the other hand, the ABCB1 gene variant rs1045642 is associated with increased peak concentrations of dabigatran and rivaroxaban, and increased bleeding frequency. Pharmacogenetic analysis of the ABCB1 gene variants rs2032582 (C.2677G>T) and rs104562 (C3435C>T) could be justified and useful in patients on rivaroxaban therapy. To prevent side effects during apixaban therapy in carriers of non-functional alleles of the CYP3A5 gene, the dose should be carefully selected and adverse reactions monitored. There is a high risk of developing adverse drug reactions when edoxaban is combined with drugs that inhibit CYP isoenzymes in homozygous carriers of non-functional alleles for the CYP3A5 gene. Conclusion: Gene polymorphism in combination with the concomitant use of inhibitors / inducers of transport proteins or enzymes responsible for drug metabolism may increase the risk of adverse events associated with alterations in DOACs.