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 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.

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment

“…Interestingly, tobacco smoking was also signi cantly associated with TRS. Approximately 60% of patients with schizophrenia are smokers [30,31], and the "self-medication" hypothesis states that nicotine consumption via tobacco smoking reduces the negative and cognitive symptoms in patients with schizophrenia [32]. Supporting this hypothesis, among patients with TRS, smokers show worse cognitive performances and more severe negative symptoms compared to nonsmokers [33] which may be indicative of self-medication behaviour to alleviate these symptoms.…”

Predicting clozapine dose required to achieve a therapeutic plasma concentration – A comparison of a population algorithm and three algorithms based on gene variant models

“…For CYP1A2 , an activity score of 1.0 was assigned to the*1A (wild type) and the *1F (higher inducibility) alleles. In smoking patients, an activity score of 2.0 was assigned for the *1F allele and in carriers of the NFIK rs28379954 allele, CYP1A2 activity was increased by 0.5 regardless of the patient’s smoking status (Lenk et al, 2023; Smith et al, 2020). The aggregate CYP3A activity score was calculated as the sum of CYP3A4 and CYP3A5 activity scores following previously described CYP3A4 combined activity models (Woillard et al, 2017).…”

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…Moreover, more than 90% of mutations that cause disease are located in such genetic regions [18]. We have found that the polymorphic NFIB gene – which encodes a nuclear protein on chromosome 9 – is also important for CYP2D6 variability [19] (Fig. 2).…”