The pharmacogenetics of warfarin in clinical practice

Varfarin je najpropisivaniji oralni antikoagulans. Postoje velike interindividualne razlike (i do 20 puta) u potrebnim dozama lijeka, štoje rezultat genetičkih i okolišnih čimbenika. Podaci dobiveni pomoću farmakogenomike, tj. ispitivanja interakcija osobnog genotipa i odgovora na lijek, mogu pomoći u postizanju optimalne uč inkovitosti lijeka i svođenju štetnih reakcija na lijek na najmanju moguću mjeru. Podaci dobiveni analizom dvaju gena, enzima za metabolizam varfarina CYP2C9 i ciljnog enzima za varfarin, podjedinice 1 vitamin K ovisne epoksid reduktaze (VKORC1), potvrdili su njihov učinak na dozu održavanja varfarina. Ispitivanjem udruženosti na razini genoma također je utvrđen slab učinak CYP4F2. Prisutnost varijantnih alela CYP2C9*2 ili CYP2C9*3, koje rezultiraju smanjenom enzimskom aktivnošću, udružena je sa značajnim smanjenjem srednje doze varfarina. Jednonukleotidni polimorfizmi VKORC1 objašnjavaju velik dio interindividualnih razlika u dozi varfarina, a VKORC1 ima otprilike tri puta jači učinak od CYP2C9. Stanje nositelja kombinacije polimorfizama VKORC1 i CYP2C9 udruženo je s teškom prekomjernom antikoagulacijom. Vrijeme do postizanja stabilnosti doze uglavnom je povezano s genotipom CYP2C9. Otpornost na varfarin vezuje se za nekoliko mis-sense mutacija u genu VKORC1. Algoritmi koji uključuju genetičke (CYP2C9 i VKORC1), demografske i kliničke čimbenike za procjenu doze varfarina mogli bi smanjiti rizik od predoziranja za vrijeme uvođenja varfarina.Warfarin is the most widely prescribed oral anticoagulant. It shows great (up to 20-fold) interindividual variability in dose requirement because of both, genetic and environmental factors. Information from pharmacogenomics, a study of the interaction of the individual\u27s genotype and drug response, can help optimize drug efficacy and minimize adverse drug reactions. Genotyping data on two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 (VKORC1), confirmed their influence on warfarin maintenance dose. Genome-wide association stu-dy also found a weak effect of CYP4F2. The presence of CYP2C9*2 or CYP2C9*3 variant alleles, which results in decreased enzyme activity, is associated with a significant decrease in the mean warfarin dose. VKORC1 single nucleotide polymorphisms (SNPs) explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold CYP2C9 effect. Carrier state of a combination of VKORC1 and CYP2C9 polymorphisms, rather than of one of these polymorphisms is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype. Warfarin resistance has been related to several missense mutatio-ns in the VKORC1. Algorithms incorporating genetic (CYP2C9 and VKORC1), de-mographic, and clinical factors to estimate warfarin dosage could potentially minimize the risk of overdose during warfarin induction

Pharmacogenomics and Pharmacovigilance

Razvoj nove discipline farmakogenetike/farmakogenomike omogućio je bolje razumijevanje genetičke predispozicije za razvoj neočekivanih reakcija na primijenjeni lijek i posljedično unaprijedio individualizaciju farmakoterapije. Postoje genetički određene interindividualne razlike u metaboličkom i transportnom kapacitetu, a time i kinetici lijekova i drugih ksenobiotika. Osim nuspojava lijekova koje su ovisne o dozi važne su nuspojave posredovane imunosnim reakcijama, a povezane su s varijabilnosti u sustavu HLA. Individualna osjetljivost prema toksičnim učincima farmakoterapije, ovisna o biotransformacijskim procesima, povezuje se s genskim polimorfizmima enzima faze I. i II. te transporterima ABC i SLC. Genski polimorfizmi također mogu imati ključnu ulogu u interakcijama lijekova. Povezivanje farmakogenomike s farmakovigilancijom ima važnu ulogu i u praćenju pojavnosti nuspojava poslije stavljanja lijeka na tržište. Regulatorna tijela uvođenjem farmakogenomičkih informacija (informacije o genomskim biljezima) u Sažetku o proizvodu (SPC) nastoje istaknuti ulogu i važnost genomskih varijabilnosti u farmakoterapiji. Također se navodi kojoj kategoriji te farmakogenetičke informacije pripadaju, tj. smatra li se testiranje obvezatnim, ima li ulogu preporuke ili je informativnog karaktera. Radi prikupljanja i implementacije znanja ustanovljeni su i različiti konzorciji među kojima prednjači Clinical Pharmacogenetics Implementation Consortium – CPIC, kao zajednički projekt The Pharmacogenomics Knowledge Base (PharmGKB) i The Pharmacogenomics Research Network koji je okupio eminentne stručnjake iz područja farmakogenetike/farmakogenomike. Glavni je cilj CPIC-a izdavanje recenziranih, ažuriranih, temeljenih na dokazima, slobodno dostupnih uputa i smjernica za primjenu lijeka prema rezultatu farmakogenetičkih analiza. Te će smjernice svakako ubrzati prijenos znanja u kliničku primjenu.The development of a new discipline, pharmacogenetics/pharmacogenomics, has enabled a better understanding of genetic predispositions for unexpected drug reaction developments, and consequently it improves the individualization of pharmacotherapy. There are certain genetic individual variations in metabolic and transport capacity, and thus the kinetics of drugs and other xenobiotics. In addition to adverse drug reactions (ADR) that are dose-dependent, significant ADR are mediated by immune reactions and are associated with variations in the HLA system. The individual sensitivity to the pharmacotherapy toxic effects, dependent on biotransformation processes, is associated with the genetic polymorphism of the phase I and phase II enzymes and ABC and SLC transporters. Genetic polymorphisms can also play a key role in drug interactions. Connecting pharmacogenomics to pharmacovigilance has a significant role in monitoring ADR during the post-marketing period. Regulatory authorities highlight the role and importance of genomic variability in pharmacotherapy by introducing pharmacogenomics (information on genomic markers) in the SPC. It also states into which category pharmacogenetics information belongs, whether pharmacogenetic testing is required, recommended or informative. In order to collect and implement pharmacogenomic knowledge different consortia have been established, including prestige Clinical Pharmacogenetics Implementation Consortium (CPIC), as a joint project of The Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network, which brought together eminent experts in the field of pharmacogenetics/pharmacogenomics. The main objectives of CPIC’s is to provide peer-reviewed, updated, evidence-based, freely available recommendations and guidelines for drug use according to results of pharmacogenetic analysis. These guidelines will certainly accelerate the knowledge transfer to the clinical use

Uloga genskog polimorfizma metaboličkih enzima P450(CYP) kao čimbenika osjetljivosti na učinkovitost i toksičnost lijeka te nastanak karcinoma

The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.Među enzimima I. faze biotransformacije sustav citokroma P450 (CYP) prednjači po katalitičkoj svestranosti i pokazuje vrlo visok stupanj polimorfnosti. Istraživanja polimorfizama gena CYP rezultirala su brojnim genetičkim informacijama koje nam pomažu u razumijevanju učinaka ksenobiotika na ljudski organizam. Ova superporodica enzima najvažniji je enzimski sustav uključen u biotransformaciju mnogih endogenih i egzogenih spojeva uključujući lijekove. Za metabolizam lijekova važan je polimorfizam CYP2C9, CYP2C19, CYP2D6 i CYP3A4/5 enzima. Među najvažnije izoforme odgovorne za biotransformaciju različitih kemijskih spojeva a posebno metaboličku aktivaciju prokarcinogena pripadaju CYP1A1, CYP1A2, CYP1B1, CYP2E1. Genska analiza ključnih enzima metabolizma lijekova pomaže u predviđanju terapijskog učinka ili razvoja štetnih nuspojava lijekova. Stoga primjena genotipizacije u kliničkoj praksi pomaže u optimizaciji i individualizaciji terapije i smanjenju medicinskih troškova. Polimorfizam metaboličkih enzima može imati važan učinak na terapiju antidepresivima, antipsihoticima, antikoagulantima, antidijabeticima, antitumorskim lijekovima te lijekovima za liječenje ulkusa i HIV-a. Podaci koje donosi toksikogenomika istražujući individualne predispozicije za karcinogene, teratogene i druge toksičke učinke ksenobiotika, pridonose rasvjetljavanju molekularnih mehanizama kojima kemijski spojevi iz okoliša ili na radnome mjestu utječu na nastanak bolesti u ljudi. Postoje značajni dokazi o povezanosti genskih polimorfizama i osjetljivosti za razvoj karcinoma. Metabolički putovi karcinogenih supstancija su kompleksni, posredovani aktivnošću različitih gena, dok pojedinačni geni najčešće imaju ograničen učinak. Stoga je multigenski pristup, uz uključivanje važnih čimbenika iz okoliša u studijama s velikim brojem ispitanika bitan za pouzdanu procjenu rizika od razvoja karcinoma

Clinical application of genotype-guided dosing of warfarin in patients with acute stroke

BACKGROUND: Patients with certain types of stroke need urgent anticoagulation and it is extremely important for them to achieve fast and stable anticoagulant effect and receive individualized treatment during the initiation of warfarin therapy. ----- METHODS: We conducted a prospective study among 210 acute stroke patients who had an indication for anticoagulation and compared the impact of CYP2C9 and VKORC1 genotype-guided warfarin dosing (PhG) with fixed dosing (NPhG) on anticoagulation control and clinical outcome between groups. ----- RESULTS: PhG achieved target INR values earlier, i.e., on average in 4.2 (4.1-4.7, 95% CI) days compared to NPhG (5.2 days [4.7-6.4, 95% CI]) (p = 0.0009), spent a higher percentage of time in the therapeutic INR range (76.3% [74.7-78.5, 95% CI] vs. 67.1% [64.5-69.6, 95% CI] in NPhG), and spent less time overdosed (INR > 3.1) (PhG 0.4 [0.1-0.7, 95% CI], NPhG 1.7 [1.1-2.3, 95% CI] days; p >0.000). PhG reached stable maintenance dose faster (10 [9.9-10.7, 95% CI] vs. 13.9 [13.3-14.7, 95% CI] days in controls; p = 0.0049) and had a better clinical outcome in relation to neurological deficit on admission as compared to NPhG. ----- CONCLUSION: We confirmed that warfarin therapy with genotype-guided dosing instead of fixed dosing reduces the time required for stabilization and improves anticoagulant control with better clinical outcome in early stages of warfarin therapy introduction among acute stroke patients, which is essential for clinical practice

The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain

Kako polimorfizmi gena citokroma P450 utječu na metabolizam i toksičnost ibuprofena i diklofenaka

Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.Interindividualne razlike u metabolizmu mogu biti važan čimbenik nastanka nuspojava te varijabilnosti u učinkovitosti lijeka. Polimorfizmi gena koji kodiraju metaboličke enzime citokrome P450 (CYP) mogu imati značajan učinak na metabolizam lijeka i toksičnost. Ovaj pregled donosi spoznaje o tome kako polimorfizam enzima CYP2C8 i CYP2C9 utječe na bioraspoloživost i kliničke ishode liječenja ibuprofenom i diklofenakom, koji se svrstavaju među najčešće propisivane nesteroidne protuupalne lijekove. Hepatotoksičnost i gastrointestinalno krvarenje najčešće su nuspojave povezane s utjecajem varijanti CYP2C8*3 i CYP2C9*2*3 na farmakokinetiku ibuprofena i diklofenaka. Na osnovi rezultata genotipizacije CYP-a mogu biti prepoznati pacijenti koji imaju povećani rizik od razvoja nuspojava te im je nužno prilagoditi dozu lijeka ili odabrati drugi lijek koji ne dijeli isti metabolički put. Osim enzima CYP, značajan utjecaj imaju i polimorfizmi gena koji kodiraju fazu II metabolizma, osobito enzimi UGT, te transporteri, poput ABCC2, koji mogu modulirati ne samo transport na barijeri jetre i žuči nego i izlučivanje bubrezima. Stoga je u budućim istraživanjima nužan poligenski pristup. Prije uvođenja genotipizacije u redovitu kliničku praksu potrebno je provesti daljnja istraživanja koja će uključivati veće fenotipski dobro definirane skupine ispitanika za procjenu učinkovitosti ove strategije u poboljšanju liječenja ibuprofenom i diklofenakom. Zbog značajne međuetničke razlike u učestalosti polimorfizama gena CYP istraživanja treba provesti među različitim rasama i populacijama

PHARMACOGENETICS AND INTERACTIONS OF ANTIDEPRESSANTS IN THE TREATMENT OF CO-MORBID ILLNESS

Patients who require long-term treatment for depression have an increased risk of experiencing drug interactions since they will take medications for and/or co-morbid illness. Antidepressants can be the object of drug interactions by other substances, or they can precipitate interactions by inhibiting enzyme pathways. There is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Genetic test suitable for the routine laboratory are now available for some important metabolizing enzymes (e.g. CY2D6, CY2C19) identifying those individuals who are slow or fast metabolizers of certain drugs. Specific antidepressants differ in the interactions with CYP450 isoenzymes and in their susceptibility to drug-drug interactions. The main focus of this article is pharmacokinetic drug interactions of antidepressants. With that specific knowledge, clinicians can improve outcomes of depressed patients, by considering the possibility of drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance