Farmakogenetika in osebna medicina
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1 Farmakogenetika in osebna medicina - od genetskega testiranja do klinične prakse prof. dr. Vita Dolžan, dr. med. Laboratorij za farmakogenetiko, Inštitut za biokemijo Medicinska fakulteta, Univerza v Ljubljani vita.dolzan@mf.uni-lj.si 1
2 Breme bolezni Strošek Genomika in osebna medicina Osebna medicina uporablja genomske pristope za preprečevanje presejanje in zgodnjo diagnostiko učinkovito zdravljenje ustrezen odmerek ustreznega zdravila ob ustrezni indikaciji za določenega bolnika ob pravem času Dovzetnost Presejanje Diagnoza Prognoza Farmakogenomika Tveganje Predsimptomatski potek Klinični znaki in progres Ginsburg & Willard, Translational Research
3 VARIABILNOST ODZIVA NA ZDRAVILA: Prepreka učinkovitemu zdravljenju Predpisovanje zdravil temelji na: - znakih in simptomih bolezni - pričakovanem odzivu Dober odgovor Ni odgovora Neželeni učinki 3
4 Interindividualna variabilnost odziva na zdravila Bolezen Skupina zdravil Delež neodzivnikov Astma beta-agonisti 40-75% Shizofrenija antipsihotiki 25-75% Depresija SSRIs, triciklični AD 20-40% Revmat. artritis temeljna zdravila 30-60% Diabetes peroralni antidiabetiki 50% Hipertenzija antihipertenzivi 30% Bolnišnični sprejemi v ZDA: 2 milijona/leto zaradi ADR (Norton, 2001) ZDA: 100,000 smrti/leto zaradi ADR (Lazarou, 1998) VB: ADR pri 1/7 hospitaliziranih bolnikov: diuretiki, opiatni analgetiki in antikoagulanti. Polovico ADR bi se dalo preprečiti (Davies, 2009) Brvar in sod., 2010: 3.7 % urgentnih sprejemov zaradi ADR 4
5 Okoljski dejavniki zdravila (interakcije) hrana, kajenje onesnaženje življensko okolje (stres) Biološki dejavniki spol, starost telesna zgradba obolenja fiziologija hormoni Variabilnost odziva na zdravljenje Zdravilo odmerek sodelovanje Genetski dejavniki encimi prenašalci tarče zdravil FARMAKOGENETIKA 5
6 GENSKA VARIABILNOST Encimi vključeni v Prenašalci zdravila Tarče zdravil in njihovih metabolizem zdravil ABC in SLC transporterji signalnih poti 1. (CYP) in 2. faza presnove Farmakokinetika Farmakodinamika variabilnost plazemskih koncentracij variabilnost odziva na zdravilo TOKSIČNOST UČINKOVITO ZDRAVLJENJE NEODZIVNOST RAZLIČEN ODZIV NA ZDRAVILO 6
7 Kdaj so farmakogenetski polimorfizmi pomembni? genetski polimorfizem vpliva na funkcijo encima in je pogost v populaciji učinkovitost zdravljenja Farmakogenetika zdravljenja s tamoksifenom Farmakogenetika zdravljenja z antipsihotiki in antidepresivi gre za zdravila z ozko terapevtsko širino napoved / prilagoditev odmerka Farmakogenetika zdravljenja z varfarinom Farmakogenetika zdravljenja s klopidogrelom možni neželeni učinki in toksičnost izbira bolj primernega zdravila Farmakogenetika zdravljenja revmatoidnega artritisa Farmakogenetika zdravljenja raka
8 CYP2C9 20 % vseh CYP v jetrih presnavlja % klinično pomembnih zdravil 1 : S - varfarin, fenitoin, NSAID, statini, sulfonilsečnine, losartan... Inhibitorji: flukonazol, izoniazid, lovastatin, amiodaron Induktorji: rifampin, barbiturati Aleli 2 polimorfizem encimska frekvenca pri aktivnost Slovencih 3 CYP2C9*1 normalna 81,5 % CYP2C9*2 R144C zmanjšana 12,2 % CYP2C9*3 I359L zmanjšana 6,3 % Herman et al, Zdrav Vestn
9 CYP2C9, presnova in vzdrževalni odmerki varfarina S-warfarin % antikoagulantnega učinka CYP2C9 R-varfarin % antikoagulantnega učinka CYP1A2, CYP2C19, CYP3A4 Kaminsky & Zhang, 1997 Herman et al, Pharmacogenomics J 2005
10 Polimorfizmi VKORC1 določajo občutljivost tarčnega encima za varfarin Varfarin inhibira cikel vitamina K
11 FDA: 16/08/ 2007 dopolnjen povzetek glavnih značilnosti zdravila za varfarin FDA: 17/09/ 2007 odobren prvi genetski test za varfarin Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test FDA: 01/22/ 2010 dopolnjen povzetek glavnih značilnosti zdravila za varfarin Genotipizacija CYP2C9 in VKORC1: priporočena, a ne zahtevana Informacija o genotipu CYP2C9 in VKORC1 pomaga pri izbiri začetnega odmerka (Tabela 5 ) Pri vseh bolnikih je potrebno nadaljnje prilagajanje odmerka glede na vrednosti PT/INR. 11
12 Prospektivne študije: genotipu prilagojeno odmerjanje v uvajalnem obdobju skrajša čas do tarčnega INR in zniža število ADR algoritmi za odmerjanje varfarina 12
13 CYP2D6 2-5 % vseh P450 v jetrih; možgani: korteks, hipokampus, cerebellum zelo polimorfen; > 130 alelov SNP, insercije/delecije, delecije gena, duplikacije gena delecije gena duplikacije gena SNP, insercije/delecije 13
14 CYP2D6: genotip / fenotip H H UM ultrahitri metabolizatorji (ultrarapid m.) ( duplikacija gena: 2-13 kopij) 1-2% bele rase, 1% Slovencev* 3.5-7% Špancev, 29% Etiopijcev EM hitri metabolizatorji (extensive m.) 2 aktivna alela IM vmesni metabolizatorji (intermediate m.) 1 manj aktiven & 1 neaktiven alel PM slabi metabolizatorji (poor m.) 2 neaktivna alela 5-10% bele rase, 7% Slovencev* N C NH 2 aleli z duplikacijo gena *1x2, *2x2, *4x2 aktivni aleli *1, *2, *35 manj aktivni aleli *9, *10, *17, *41 NH 2 + neaktivni aleli (*0) *3, *4, *5, *6, *7, *8, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38... * Dolžan V in sod
15 Fenotipizacija ali genotipizacija? Fenotipizacija (vpliv genotipa in ostalih dejavnikov) Preiskovanca obremenimo z učinkovino, ki se presnavlja izključno preko preučevanega encima -Zbiramo vzorce krvi (plazma) / urina - v eni točki ali v odvisnosti od časa - Farmakokinetična analiza učinkovine / presnovka - Razmerje koncentracij presnovka / učinkovine je merilo za hitrost presnove preko določenega P450 Genotipizacija (samo vpliv genotipa) Odvzamemo vzorev krvi (> 1 ml), sline ali bukalni bris Izoliramo jedrno DNA -Specifične odseke DNA pomnožimo z verižno reakcijo polimerrizacije (PCR _ polymerase chain reaction) - Detekcija sprememb v nukleotidnem zaporedju (v realnem času, z restrikcijsko analizo, s sekvenčno analizo)
16 CYP2D6 presnova > 30 zdravil: antidepresivi, antipsihotiki, antiepileptiki, antiaritmiki... aktivacija kodeina, tramadola, oksikodona, tamoksifena, EM: X hitrejša hidroksilacija kot PM prepočasna presnova povečano tveganje za ADR ob običajnih odmerkih neučinkovitost pro-zdravil prehitra presnova neučinkovitost običajnih odmerkov toksičnost pro-zdravil 16
17 % standardnega odmerka 17 Kirchheiner et al., Mol Psychiatry 2004 Prilagoditev odmerkov antidepresivov in antipsihotikov glede na genotip CYP2D UM EM 50 IM PM 0
18 Testiranje CYP2D6 v psihiatriji kaj kaže klinična praksa Meta analiza (2010) analitična zanesljivost (analitical validity) farmakogenetskih testov je zelo dobra ni zadostnih dokazov o klinični zanesljivosti (clinical validity) in uporabnosti (clinical utility) obstajajo zadovoljivi dokazi glede povečanega tveganja za EPS pri PM za CYP2D6 genetsko testiranje CYP2D6 ni imelo signifikanega vpliva na odgovor na zdravljenje Zaključek: "The potential benefit of CYP450 testing is therefore still uncertain and it would be premature to recommend the use of pharmacogenetic testing for adults with schizophrenia. 18
19 Signalna pot serotonina in dopamina Alela S (P=0,022) in S + Lg (p=0,004) - boljši odgovor na zdravljenje z antipsihotiki Serotoninski transporter SLC6A4 (SERT ali 5-HTT) 5-HTTLPR*La/Lg/S serotoninski receptor A1 5-HTR1A C-1019G G-protein GNB3 C825T Serotonergičen nevron dopaminski receptor DRD2 C1167G (Ser311Cys) 19
20 CYP2D6 in aktivacija tamoksifena Jin, Y. et al. J Natl Cancer Inst 2005;97:30-39 CP
21 Plasma 100 Endoxifen (nm) Genotip CYP2D6 in plazemske koncentracije endoksifena P<0.001, r 2 =0.24 Wt/Wt Wt/*4 *4/*4 CYP2D6*4 (najpogostejši nefunkcionalni alel pri PM) Jin Y et al: J Natl Cancer Inst 97:30, 2005
22 Genotip CYP2D6 in preživetje brez relapsa (relapse-free survival) pri bolnicah s Ca dojke na tamoksifenu 100 % CYP2D6 *4/*4 CYP2D6 *4/WT CYP2D6 WT/WT 20 P= Years after randomization Goetz et al J Clin Oncol. 2005;23(36):
23 Inhibition of CYP2D6 Affects Endoxifen Concentrations Plasma 80 Endoxifen (nm) Wt/Wt, no inhibitor Venlafaxine Sertraline Paroxetine *4/*4, no inhibitor Jin Y et al: J Natl Cancer Inst 97:30, 2005
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27 CYP2C19 presnavlja / inaktivira 5 % klinično pomembnih zdravil: inhibitorji protonske črpalke, antiepileptiki, antidepresivi aktivacija klopidogrela inhibitorji: kloramfenikol, cimetidin, ketokonazol, omeprazol... inducers: karbamazepin, prednizon, rifampicin aleli polimorfizmi encimska frekvenca pri aktivnost Slovencih CYP2C19*1 - - normalna CYP2C19* G>A splice defect neaktiven 15,9 % CYP2C19* G>A W212X neaktiven 0,4 % CYP2C19*17-806C>T prepisovanje povečana 17 % Swedish PMs: 3-5% Kavkazijcev, % Azijcev
28 CYP2C19 in inhibitorji protonske črpalke Hitrejše celjenje želodčnih razjed in bolj uspešna eradikacijska terapija pri PM za CYP2C19 % ozdravitve Hitri metabolizatorji (EM) 28.6% Vmesni metabolizatorji (IM) 60% Slabi metabolizatorji (PM) 100%
29 CYP2C19 in klopidogrel PM: two reduced function alleles IM: one reduced function allele EM: no variant allele UM: one or two *17 Mega et al, N Engl J Med 2008 Carriers: at least one variant allele: *2, *3, *4, *5, *8 (IM + PM) *Outcome: a composite death from cardiovascular causes, myocardial infarction or stroke
30 The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel, or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.
31 label update approved on 05/06/2011 (PDF) for PLAVIX, NDA no
32 32
33 Clinical Pharmacogenetics Implementation Consortium Guidelines... to provide guidance to clinicians so that pharmacogenetic tests can be used in the clinic... current list of gene/drug pairs with CPIC guidelines. > 65 zdravil
34 Kateri odmerek je pravi za tvojega bolnika? Prej: En odmerek za vse Sedaj in v prihodnje: odmerjanje na podlagi genotipa Personalizacija farmakoterapije
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