Impact of CYP1A, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NFIB genotypes on clozapine serum concentration in smokers and nonsmokers.

Background: Clozapine is the most effective drug for schizophrenia and is the only drug indicated for use in patients with treatment resistance. The therapeutic range of clozapine is narrow with extensive interindividual differences in serum levels at similar dosing, mainly due to variability in hepatic metabolism mediated by several cytochrome P450 (CYP) enzymes. Tobacco smoking is the most important environmental factor determining clozapine metabolism, while the effect of pharmacogenetic variability is unclear.

Objectives: To investigate the impact of CYP1A, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NFIB alleles on clozapine levels stratified by smoking status in a large patient population.

Design: This is a retrospective naturalistic/observational study.

Methods: The study population was included from the therapeutic drug monitoring/pharmacogenetics service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, during January 2005-November 2024. We assessed the influence of CYP1A rs247229 T, CYP1A2*1F, CYP2C19, CYP2D6, CYP3A4*22 and CYP3A5*3, and NFIB rs28379954 C genetic variants on clozapine dose-adjusted serum concentrations (CD) in both smokers and nonsmokers.

Results: The study comprised 663 participants (55% smokers). CYP1A T variant was significantly associated with reduced clozapine serum levels, compared to CYP1A CC genotype, both among smokers (-15%, p = 0.010) and nonsmokers (-16%; p = 0.011). Moreover, among smokers, participants with NFIB C variant had 40% reduced clozapine CD compared to participants with NFIB TT (p < 0.001), whereas carriers of the CYP3A5*1/*1 genotype exhibited a 37% lower clozapine CD compared to CYP3A5*3/*3 carriers (p = 0.024) among nonsmokers. CYP1A2*1F, CYP2C19, CYP2D6, and CYP3A4*22 variants did not have any significant impact on clozapine CD, regardless of smoking habits.

Conclusion: The CYP1A T, NFIB C, and CYP3A5*1 alleles have significant impact on clozapine serum levels. Incorporating genotype information for these variants, together with patient smoking status, would improve algorithms for precision dosing of clozapine.