dc.date.accessioned | 2022-12-12T17:23:37Z | |
dc.date.available | 2022-12-12T17:23:37Z | |
dc.date.created | 2022-11-17T11:02:28Z | |
dc.date.issued | 2022 | |
dc.identifier.citation | Lenk, Hasan Çağın Smith, Robert Løvsletten O'Connell, Kevin Sean Jukić, Marin M. Kringen, Marianne K. Andreassen, Ole Ingelman-Sundberg, Magnus Molden, Espen . Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. Clinical and Translational Science (CTS). 2022 | |
dc.identifier.uri | http://hdl.handle.net/10852/98110 | |
dc.description.abstract | Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (−48%; p < 0.0001) and nonsmokers (−35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia. | |
dc.language | EN | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits | |
dc.title.alternative | ENEngelskEnglishImpact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits | |
dc.type | Journal article | |
dc.creator.author | Lenk, Hasan Çağın | |
dc.creator.author | Smith, Robert Løvsletten | |
dc.creator.author | O'Connell, Kevin Sean | |
dc.creator.author | Jukić, Marin M. | |
dc.creator.author | Kringen, Marianne K. | |
dc.creator.author | Andreassen, Ole | |
dc.creator.author | Ingelman-Sundberg, Magnus | |
dc.creator.author | Molden, Espen | |
cristin.unitcode | 185,53,0,0 | |
cristin.unitname | Institutt for klinisk medisin | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 2075416 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Clinical and Translational Science (CTS)&rft.volume=&rft.spage=&rft.date=2022 | |
dc.identifier.jtitle | Clinical and Translational Science (CTS) | |
dc.identifier.pagecount | 0 | |
dc.identifier.doi | https://doi.org/10.1111/cts.13422 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1752-8054 | |
dc.type.version | PublishedVersion | |