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

<jats:sec> <jats:title>Background:</jats:title> <jats:p>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 <jats:italic toggle="yes">N</jats:italic>-desmethylclozapine (<jats:italic toggle="yes">N</jats:italic>-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on <jats:italic toggle="yes">N</jats:italic>-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>A total of 763 patients with steady-state serum concentrations of CLZ and <jats:italic toggle="yes">N</jats:italic>-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 <jats:italic toggle="yes">N</jats:italic>-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The dose-adjusted <jats:italic toggle="yes">N</jats:italic>-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (<jats:italic toggle="yes">P</jats:italic> < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted <jats:italic toggle="yes">N</jats:italic>-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (<jats:italic toggle="yes">P</jats:italic> = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted <jats:italic toggle="yes">N</jats:italic>-DMC levels (<jats:italic toggle="yes">P</jats:italic> = 0.873).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in <jats:italic toggle="yes">N</jats:italic>-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in <jats:italic toggle="yes">N</jats:italic>-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 <jats:italic toggle="yes">N</jats:italic>-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.</jats:p> </jats:sec>