CYP2D6 Genotypes Do Not Affect Clozapine Levels in a Large, Multicenter Cohort: Time Has Come to Revise Food and Drug...

The US Food and Drug Administration (FDA) package insert for clozapine states that cytochrome P450 (CYP) 2D6 is important in clozapine metabolism, implying that CYP2D6 genotypes should be considered in clozapine dosing. We investigated differences for clozapine concentration-to-dose (C/D) ratios, as a pharmacokinetic measure, in relation to CYP2D6 phenotype.

Linear mixed-effect regression models were applied to investigate the association between genotype-predicted CYP2D6 metabolizer phenotypes and C/D ratios including the effects of age, sex, smoking, and sampling time in a pooled sample of three cohorts, both without and with adjusting for the interaction between cohort and CYP2D6 phenotype, as well as in separate models stratified by cohort.

We included 897 patients from three cohorts with a total of 10 428 clozapine and norclozapine measurements. We found no association between CYP2D6 phenotypes and clozapine or norclozapine C/D ratios or clozapine-to-norclozapine ratios in the pooled sample with or without adjustment for the interaction between cohort and CYP2D6 phenotype nor when analyzing three cohorts separately (P>.05 in all cases). Older patients and females had higher C/D ratios of clozapine and norclozapine (P<.001, P<.001, P<.001 and P=.02), whereas smokers had lower C/D ratios of clozapine and norclozapine as well as clozapine-to-norclozapine ratios (P<.001 for all three).

We reported no association between CYP2D6 genotype-predicted phenotypes and clozapine pharmacokinetics. Dose adjustment based on CYP2D6 genotyping is unlikely to be helpful in managing clozapine-treated patients. We propose that the current FDA package insert should be updated to avoid misleading prescribers.