Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits
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 sign...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-01-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13422 |
| _version_ | 1797952025271468032 |
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| author | Hasan Çağın Lenk Robert Løvsletten Smith Kevin S. O'Connell Marin M. Jukić Marianne Kristiansen Kringen Ole A. Andreassen Magnus Ingelman‐Sundberg Espen Molden |
| author_facet | Hasan Çağın Lenk Robert Løvsletten Smith Kevin S. O'Connell Marin M. Jukić Marianne Kristiansen Kringen Ole A. Andreassen Magnus Ingelman‐Sundberg Espen Molden |
| author_sort | Hasan Çağın Lenk |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T22:39:52Z |
| format | Article |
| id | doaj.art-b404641d026a4bb681d473f000373fe3 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-10T22:39:52Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-b404641d026a4bb681d473f000373fe32023-01-16T08:07:54ZengWileyClinical and Translational Science1752-80541752-80622023-01-01161627210.1111/cts.13422Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habitsHasan Çağın Lenk0Robert Løvsletten Smith1Kevin S. O'Connell2Marin M. Jukić3Marianne Kristiansen Kringen4Ole A. Andreassen5Magnus Ingelman‐Sundberg6Espen Molden7Center for Psychopharmacology Diakonhjemmet Hospital Oslo NorwayCenter for Psychopharmacology Diakonhjemmet Hospital Oslo NorwayDivision of Mental Health and Addiction, NORMENT Centre Oslo University Hospital Oslo NorwaySection of Pharmacogenetics, Department of Physiology and Pharmacology Karolinska Institutet Stockholm SwedenCenter for Psychopharmacology Diakonhjemmet Hospital Oslo NorwayDivision of Mental Health and Addiction, NORMENT Centre Oslo University Hospital Oslo NorwaySection of Pharmacogenetics, Department of Physiology and Pharmacology Karolinska Institutet Stockholm SwedenCenter for Psychopharmacology Diakonhjemmet Hospital Oslo NorwayAbstract 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.https://doi.org/10.1111/cts.13422 |
| spellingShingle | Hasan Çağın Lenk Robert Løvsletten Smith Kevin S. O'Connell Marin M. Jukić Marianne Kristiansen Kringen Ole A. Andreassen Magnus Ingelman‐Sundberg Espen Molden 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 |
| title | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits |
| title_full | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits |
| title_fullStr | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits |
| title_full_unstemmed | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits |
| title_short | Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits |
| title_sort | impact of nfib and cyp1a variants on clozapine serum concentration a retrospective naturalistic cohort study on 526 patients with known smoking habits |
| url | https://doi.org/10.1111/cts.13422 |
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