o:29312 Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera doktorska disertacija Meta-analysis of the data on differences in the exposure to psychiatric drugs between poor and normal cYP2C19/CYP2D6 metabolizers : doctoral dissertation sr Postoji mogućnost da genetski predodređene razlike između osoba u kapacitetu CYP450enzima mogu uticati na farmakoterapiju u psihijatriji. Cilj ovog istraživanja bio je preciznakvantifikacije uticaja CYP2C19/CYP2D6 fenotipa na izloženost antidepresivima iantipsihoticima metodom meta-analize odnosa srednjih vrednosti. Drugi cilj bio jeispitivanje uticaja CYP2C19 fenotipa na efikasnost i podnošljivost antidepresiva pomoćukliničke studije u kojoj su hospitalizovani pacijenti praćeni četiri nedelje.Serija meta-analiza podataka iz 94 jedinstvene studije na ukupno 8379 precizno jekvantifikovala povećanu izloženost escitalopramu (+163%; 95%CI: +140%, 189%;n=1262, p<0,0001) i sertralinu (+38%; 95%CI: +27%, +51%; n=917, p<0,0001) kod osobasa genetski predviđenim smanjenim kapacitetom CYP2C19 enzima, kao i povećanuizloženost risperidonu (+36%; 95%CI: +28%, +44%; n=1492, p<0,0001), aripiprazolu(+48%; 95%CI: +41%, +57%; n=1038, p<0,0001) i haloperidolu (+68%; CI95%: 40%,102%; n=423, p<0.0001) kod osoba sa genetski predviđenim smanjenim kapacitetomCYP2D6 enzima. Klinička studija demonstrirala je da su, u toku četiri nedelje, osobe sasporijim CYP2C19 metabolizmom imale 36% (95%CI: 20-52%, p<0,0001) manje izraženopoboljšanje simptoma depresije (praćeno Hamilton skalom za depresiju) i značajno većiintenzitet neželjenih efekata vezanih za gastrointestinalni (q=0,002) i centralni nervnisistem (q=0,045) što je mereno Toronto skalom, u odnosu na kontrolne osobe.Zbog visoke preciznosti kvantifikacije, rezultati meta-analiza mogu poslužiti kao osnova zakliničke smernice za precizno doziranje ispitivanih lekova na osnovu CYP2C19/CYP2D6genotipa. Takođe, rezultati kliničke studije naglašavaju da CYP2C19 genotip može bitiklinički važna informacija u psihijatrijskoj praksi. Genetically predicted interindividual differences in activites of CYP450 enzymes maysignificantly influence pharmacotherapy in psychiatry. The aim of this research was toprecisely quantify the influence of CYP2C19/CYP2D6 phenotype on the exposure toantidepressants and antipsychotics with ratio-of-means meta-analysis. Other aim was todetermine the influence of CYP2C19 phenotype on the efficacy and tolerability ofantidepressants in the clinical study of inpatients that were monitored for four weeks.Meta-analyses of the data from 94 unique studies and 8379 participants preciselyquantified the increased exposure to escitalopram (+163%; 95%CI: +140%, 189%;n=1262, p<0.0001) and sertraline (+38%; 95%CI: +27%, +51%; n=917, p<0.0001) inparticipants with genetically predicted decreased CYP2C19 capacity; and increasedexposure to risperidon (+36%; 95%CI: +28%, +44%; n=1492, p<0.0001), aripiprazole(+48%; 95%CI: +41%, +57%; n=1038, p<0.0001) and haloperidol (+68%; CI95%: 40%,102%; n=423, p<0.0001) in participants with genetically predicted decreased CYP2D6enzyme capacity. Clinical study revealed that, during 4 weeks, patients with decreasedCYP2C19 activity had 36% (95%CI: 20-52%, p<0.0001) less pronounced depressionsymptom improvement (monitored with Hamilton depression rating scale), and significantlyhigher intensity of central nervous system (q=0.002) and gastrointestinal (q=0.042)adverse reactions (monitored with Toronto adverse reaction scale), compared to controls.Due to high quantification precision, results of the meta-analyses may serve as a basis forprecise dosing guidelines, for examined drugs, that are based on CYP2C19/CYP2D6genotype. Also, clinical study results suggest that CYP2C19 genotype may be usefulclinical information in psychiatric practice. Farmaceutske nauke - (Farmakologija) / Pharmacy - (Pharmacology) Datum odbrane: 21.10.2022. Antidepresivi, Antipsihotici, CYP2C19, CYP2D6, Farmakogenetika, Precizna medicina, Meta-analiza, Klinička studija Antidepressants, Antipsychotics, CYP2C19, CYP2D6, Pharmacogenetics, Precise medicine, Meta-analysis, Clinical study 615.214:577.2(043.3) 91552100 80769289 91552101 9082 2023-05-11T10:03:11.053Z 45 no 46 Filip, 1993- Milosavljević 28074855 2022 63 mentor Marin, 1986- Jukić 25498983 2022 63 član komisije Vesna, 1964- Pešić 12669031 2022 63 član komisije Dušanka, 1983- Stanić 22159719 2022 63 član komisije Čedo, 1966- Miljević 22571367 2022 63 član komisije Ana, 1979- Starčević 15203175 2022 63 član komisije Zorana, 1974- Pavlović 54563593 2022 81 str. 8705790 http://phaidrabg.bg.ac.rs/o:29312 no yes 11 2023-05-11T10:03:11.320Z 70 11 1067094 Antidepresivi, Antipsihotici, CYP2C19, CYP2D6, Farmakogenetika, Preciznamedicina, Meta-analiza, Klinička studija Antidepressants, Antipsychotics, CYP2C19, CYP2D6, Pharmacogenetics,Precise medicine, Meta-analysis, Clinical study 615.214:577.2(043.3) 1738 11A13 2022