Impact of NFIB and CYP1A variants on clozapine serum concentration-A retrospective naturalistic cohort study on 526 patients with known smoking habits.

Autor: Lenk HÇ; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway., Løvsletten Smith R; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Division of Mental Health and Addiction, NORMENT Centre, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., O'Connell KS; Division of Mental Health and Addiction, NORMENT Centre, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Jukić MM; Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.; Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia., Kringen MK; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway., Andreassen OA; Division of Mental Health and Addiction, NORMENT Centre, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Ingelman-Sundberg M; Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Molden E; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2023 Jan; Vol. 16 (1), pp. 62-72. Date of Electronic Publication: 2022 Oct 07.
DOI: 10.1111/cts.13422
Abstrakt: 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.)
Databáze: MEDLINE
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