Farmakogenomička testiranja kandidata za transplantaciju bubrega i terapijski ishodi

Cilj istraživanja: Cilj ovoga rada jest procijeniti postoji li i koliki je potencijal farmakogenetike u području optimizacije imunosupresivne terapije u transplantaciji bubrega. Nadalje, cilj je i procijeniti ulogu farmakogenetike u ovom kliničkom području. Hipoteza je da genetičko nasljeđe može značajno izmijeniti međusobne interakcije imunosupresivnih lijekova i organizma. Materijali i metode: Učinjen je pregled dostupne relevantne literature, a posebna je pozornost pri tome bila posvećena istraživanju udžbeničke literature i stručnih smjernica. Potom je slijedilo pretraživanje bibliografskih baza podataka (PubMed) i baza podataka sintetiziranog znanja (PharmGKB), koje je uključivalo sljedeće ključne pojmove u različitim kombinacijama: farmakogenomika, imunosupresivni lijekovi, transplantacija bubrega, polimorfizam, mikofenolat, CNI, ciklosporin, takrolimus, mTOR inhibitor, sirolimus, everolimus, CYP3A4, CYP3A5, farmakodinamika, prijenosnici. U obzir je uzimana literatura objavljena u razdoblju od 2010. do 2020., uz manje iznimke vezane za udžbenike i pojedina pionirska istraživanja. Rezultati: Pregledana su značajnija istraživanja u kojima je metodologija temeljena na kombiniranju informacije o dozi lijeka s podacima dobivenima genotipizacijom primatelja bubrežnog presatka za polimorfizme pojedinačnih nukleotida (engl. Single-Nucleotide Polymorphism, SNP) gena koji kodiraju metaboličke enzime i prijenosnike imunosupresivnih lijekova, kao i pregledni radovi koji se na takva i slična istraživanja referiraju. Pronađeno je kako smjernice konzorcija za implementaciju kliničke farmakogenetike (engl. Clinical Pharmacogenetics Implementation Consortium, CPIC) otvaraju mogućnost da genotipom gena natporodice citokroma P450, porodica 3, potporodica A, člana 5 (engl. Cytochrome P450 Family 3 Subfamily A Member 5, CYP3A5) usmjeravano doziranje takrolimusa poboljša kliničke ishode jer se njime može brže nakon transplantacije dostići ciljne koncentracije takrolimusa u krvi, čak i kada se primjenjuje titracija terapijskim praćenjem lijeka (engl. Therapeutic Drug Monitoring, TDM). Brže postizanje ciljnih koncentracija može potencijalno umanjiti rizik odbacivanja presatka uslijed premale ili toksičnost uslijed prevelike izloženosti lijeku. U smjernicama se oprezno pristupa ideji zamjenjivanja TDM-a genotipizacijom CYP3A5, zbog toga što drugi faktori (poput demografskih, interakcija lijek-lijek, genetičkih varijacija koje bi utjecale na farmakodinamiku) također mogu utjecati na doziranje takrolimusa. Takrolimus je jedini takav imunosupresiv, ukoliko zanemarimo smjernice za doziranje azatioprina (prema genotipu tiopurin metiltransferaze (engl. thiopurine S-methyltransferase, TPMT)) čija je primjena u transplantaciji već dugi niz godina zanemariva. Daleko je manje farmakogenetički istraživana farmakodinamika imunosupresiva primjenjivanih u transplantaciji bubrega, a po pitanju jedinog farmakodinamičkog polimorfizma koji je značajnije istraživan, onoga gena koji kodira enzim inozin-5'-monofosfat-dehidrogenazu (engl. inosine-5'-monophosphate dehydrogenase, IMPDH), nije postignut širi konsenzus po pitanju odabira farmakogenetičkog biljega i njegove kliničke primjene. Zaključak: Trenutno postoje ograničenja za rutinsku kliničku primjenu farmakogenomike u odabiru imunosupresivnog liječenja za bolesnike kandidate za transplantaciju bubrega. Izazov u farmakogenomici imunosupresivnih lijekova nepostojanje je dostatnih kliničkih dokaza o prednosti provedbe doziranja na temelju testova genotipizacije. Da bi se znanstvene spoznaje o važnosti polimorfizama primijenile u individualizaciji terapije nužno je provesti dodatne kliničke studije o utjecaju farmakogenetike na preživljenje presatka ili na opće stanje bolesnika. Objašnjenje za poziciju koju farmakogenomika trenutno zauzima u području imunosupresivne terapije u transplantaciji bubrega, djelomično može biti u tomu da se većina najčešće upotrebljavanih imunosupresiva metabolizira putem enzima natporodice citokroma P450, porodica 3, potporodica A, član 4 (engl. Cytochrome P450 Family 3 Subfamily A Member 4, CYP3A4) čija je ekspresija neovisno o genotipu vrlo varijabilna inter- i intraindividualno te je složenost predviđanja farmakokinetike neminovna. Na to, između ostalog, utječu lijek-lijek interakcije, varijacije u genima koji utječu na aktivnost CYP3A te epigenski faktori.Objectives: The aim of this thesis is to assess whether there is, and to what extent, a potential for pharmacogenetics in the field of immunosuppressive therapy optimization in kidney transplant recipients. The aim is also to determine what role pharmacogenetics currently plays in this area. The hypothesis is that genetic inheritance can significantly alter the interactions between immunosuppressive drugs and the organism. Materials and methods: A review of the available relevant literature was made, and special attention was paid to the research of textbook literature and professional guidelines. This was followed by a search of bibliographic databases (PubMed) and synthesized knowledge databases (PharmGKB), which included the following key terms in different combinations: pharmacogenomics, immunosuppressive drugs, kidney transplantation, polymorphism, mycophenolate, CNI, cyclosporine, tacrolimus, mTOR inhibitor, sirolimus, everolimus, CYP3A4, CYP3A5, pharmacodynamics, transporters. The literature published in the period from 2010 to 2020 was taken into account, with minor exceptions related to textbooks and individual pioneering research. Results: Significant studies in which the methodology is based on combining drug dose information with data obtained by renal graft recipients genotyping for Single-Nucleotide Polymorphisms (SNPs) in genes encoding metabolic enzymes and transporters of immunosuppressive drugs have been reviewed, as well as review papers referring to such and similar studies. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines have been found to open the possibility that Cytochrome P450 Family 3 Subfamily A Member 5, CYP3A5 genotype-directed dosing of tacrolimus improves clinical outcomes because it could help reach the target tacrolimus blood concentrations faster after transplantation, even when therapeutic drug monitoring (TDM) titration is applied. Achieving target concentrations faster can potentially reduce the risk of graft rejection due to too low or toxicity due to too high drug exposure. The guidelines cautiously approach the idea of replacing TDM with CYP3A5 genotyping, because other factors (such as demographics, drug-drug interactions, genetic variations that would affect the pharmacodynamics) may also affect tacrolimus dosing. Tacrolimus is the only immunosuppressive drug for which guidelines on dosing according to genotype exist, disregarding the guidelines for dosing of azathioprine (according to thiopurine S-methyltransferase (TPMT) genotype), use of which in transplantation has been negligible for many years. The pharmacodynamics of immunosuppressants used in kidney transplantation is far less researched, and for the only pharmacodynamic polymorphism that has been significantly researched, the inosine-5'-monophosphate dehydrogenase gene (IMPDH), a consensus on the choice of pharmacogenetic marker and its clinical application has yet to be reached. Conclusion: Currently, significant limitations exist for the routine application of pharmacogenomics in the selection of immunosuppressive treatment for kidney transplant recipients. A challenge in the pharmacogenomics of immunosuppressive drugs is the lack of sufficient clinical evidence on the benefit of dosing based on genotyping tests. In order to apply scientific knowledge about the importance of polymorphisms in therapy individualization of kidney transplant candidates, it is necessary to conduct additional clinical studies on the impact of pharmacogenetics on graft survival or general patient condition. The explanation for the current position of pharmacogenomics in the field of immunosuppressive therapy in renal transplantation may be partly consequence of the fact that most commonly used immunosuppressants are metabolized by the enzyme Cytochrome P450 Family 3 Subfamily A Member 4, CYP3A4, since expression of this enzyme is, regardless of genotype, highly variable inter- and intraindividually. This is influenced, among other things, by drug-drug interactions, variations in genes that affect CYP3A activity, and epigenetic factor