| Abstract | 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. |
| Abstract (english) | 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 factors |
