Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid—Indications of a Presystemic Interaction Mechanism

Abstract

Background: Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. Methods: A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. Results: The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). Conclusions: The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients—a genome-wide association study adjusting for smoking habits

“…The present study replicated the previously identified locus on chromosome 4 for both N-desmethylclozapine and the CLZ-to-N-desmethylclozapine metabolic ratio, independent of smoking habits 9,24 . When adjusting for known smoking habits, which have a major effect on CLZ metabolism 13,14 , we identified a novel locus in the NFIB gene (rs28379954 T>C) associated with a significant reduction in CLZ serum concentrations.…”

“…In their study, however, smoking habits data were not available, and polygenic risk scores for smoking were therefore used as a proxy measure of smoking habits instead. Notably, cigarette smoking has been shown to reduce CLZ levels by~30-50% by inducing CYP1A1/1A2 [23][24][25] , and up to 60% of individuals with schizophrenia are smokers 36 . Given the large effect of smoking on CLZ metabolism, and the high prevalence of smoking in people with schizophrenia, the differences in accounting for smoking habits may explain the discrepancy between the studies.…”

“…Tobacco smoke reduces the serum concentration of CLZ by~30-50% due to polycyclic aromatic hydrocarbons inducing gene transcription of drugmetabolizing enzymes, e.g., CYP1A enzymes [23][24][25] . Thus, information on smoking habits is crucial when studying factors that may influence the CLZ serum concentrations.…”

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview

“…[30] Valproic acid, instead of being an inhibitor of clozapine metabolism, can be an inducer in some patients. Studies suggest that when valproic acid acts as an inducer, it mainly induces norclozapine metabolism [31,[36][37][38] but can sometimes contribute to the patient becoming a UM who needs very high clozapine doses. [39] Norclozapine is clozapine's main metabolite and has no antipsychotic efficacy but may contribute to adverse drug reactions.…”

Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits

“…Therapeutic drug monitoring measurements were excluded for patients co‐medicated with CYP enzyme inducers (phenobarbital, phenytoin, and carbamazepine) or the antidepressant CYP1A2/3A4 inhibitor fluvoxamine. Additionally, measurements with co‐medication of valproate were excluded from statistical analysis of N ‐desmethylclozapine‐to‐clozapine ratio due to its specific interaction with this variable 26 . Patients with inconsistent information about smoking habits for consecutive TDM requests during the time span of the study period were excluded.…”