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Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits
dc.creator | Lenk, Hasan Çağın | |
dc.creator | Løvsletten Smith, Robert | |
dc.creator | O'Connell, Kevin | |
dc.creator | Jukić, Marin | |
dc.creator | Kringen, Marianne Kristiansen | |
dc.creator | Andreassen, Ole | |
dc.creator | Ingelman-Sundberg, Magnus | |
dc.creator | Molden, Espen | |
dc.date.accessioned | 2022-10-18T15:14:51Z | |
dc.date.available | 2022-10-18T15:14:51Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 1752-8054 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/4290 | |
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. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | |
dc.publisher | John Wiley and Sons Inc | |
dc.relation | South- Eastern Norway Regional Health Authority (Grant number 2020019) | |
dc.relation | The European Union's Horizon 2020 research and innovation program (Grant Agreement 964874/REALMENT) | |
dc.relation | The Swedish Research Council (Grant number 2021- 02732) | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | Clinical and Translational Science | |
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.type | article | |
dc.rights.license | BY-NC-ND | |
dc.citation.rank | M22 | |
dc.identifier.wos | 000864759100001 | |
dc.identifier.doi | 10.1111/cts.13422 | |
dc.identifier.scopus | 2-s2.0-85139426402 | |
dc.identifier.fulltext | http://farfar.pharmacy.bg.ac.rs/bitstream/id/10460/Impact_of_NFIB_pub_2022.pdf | |
dc.type.version | publishedVersion |