TY  - JOUR
AU  - Lenk, Hasan Çağın
AU  - Løvsletten Smith, Robert
AU  - O'Connell, Kevin
AU  - Jukić, Marin
AU  - Kringen, Marianne Kristiansen
AU  - Andreassen, Ole
AU  - Ingelman-Sundberg, Magnus
AU  - Molden, Espen
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4290
AB  - 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.
PB  - John Wiley and Sons Inc
T2  - Clinical and Translational Science
T1  - Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits
DO  - 10.1111/cts.13422
ER  - 

@article{
author = "Lenk, Hasan Çağın and Løvsletten Smith, Robert and O'Connell, Kevin and Jukić, Marin and Kringen, Marianne Kristiansen and Andreassen, Ole and Ingelman-Sundberg, Magnus and Molden, Espen",
year = "2022",
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.",
publisher = "John Wiley and Sons Inc",
journal = "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",
doi = "10.1111/cts.13422"
}

Lenk, H. Ç., Løvsletten Smith, R., O'Connell, K., Jukić, M., Kringen, M. K., Andreassen, O., Ingelman-Sundberg, M.,& Molden, E.. (2022). Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science
John Wiley and Sons Inc..
https://doi.org/10.1111/cts.13422

Lenk HÇ, Løvsletten Smith R, O'Connell K, Jukić M, Kringen MK, Andreassen O, Ingelman-Sundberg M, Molden E. Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science. 2022;.
doi:10.1111/cts.13422 .

Lenk, Hasan Çağın, Løvsletten Smith, Robert, O'Connell, Kevin, Jukić, Marin, Kringen, Marianne Kristiansen, 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" in Clinical and Translational Science (2022),
https://doi.org/10.1111/cts.13422 . .

TY  - JOUR
AU  - Smith, Robert
AU  - Tveito, Marit
AU  - Kyllesø, Lennart
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
AU  - Andreassen, Ole
AU  - Molden, Espen
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3805
AB  - Background: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. Methods: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. Results: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. Conclusions: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.
PB  - Elsevier B.V.
T2  - Schizophrenia Research
T1  - Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders
VL  - 228
SP  - 590
EP  - 596
DO  - 10.1016/j.schres.2020.11.025
ER  - 

@article{
author = "Smith, Robert and Tveito, Marit and Kyllesø, Lennart and Jukić, Marin and Ingelman-Sundberg, Magnus and Andreassen, Ole and Molden, Espen",
year = "2021",
abstract = "Background: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. Methods: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. Results: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. Conclusions: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.",
publisher = "Elsevier B.V.",
journal = "Schizophrenia Research",
title = "Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders",
volume = "228",
pages = "590-596",
doi = "10.1016/j.schres.2020.11.025"
}

Smith, R., Tveito, M., Kyllesø, L., Jukić, M., Ingelman-Sundberg, M., Andreassen, O.,& Molden, E.. (2021). Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders. in Schizophrenia Research
Elsevier B.V.., 228, 590-596.
https://doi.org/10.1016/j.schres.2020.11.025

Smith R, Tveito M, Kyllesø L, Jukić M, Ingelman-Sundberg M, Andreassen O, Molden E. Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders. in Schizophrenia Research. 2021;228:590-596.
doi:10.1016/j.schres.2020.11.025 .

Smith, Robert, Tveito, Marit, Kyllesø, Lennart, Jukić, Marin, Ingelman-Sundberg, Magnus, Andreassen, Ole, Molden, Espen, "Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders" in Schizophrenia Research, 228 (2021):590-596,
https://doi.org/10.1016/j.schres.2020.11.025 . .