The Impact of Once Daily Dosing on Protein Binding of Clozapine and Norclozapine

Abstract

Purpose/Background: Clozapine and norclozapine are highly protein bound. Currently, clozapine is increasingly prescribed once daily (QD). Higher (once daily) doses may theoretically lead to saturation of protein binding of (nor)clozapine, resulting in increased unbound fractions. This study investigated whether protein binding of clozapine and norclozapine becomes saturated at higher concentrations. Secondly, the correlation between unbound (nor)clozapine fractions and alpha-1 acid glycoprotein (AGP) concentrations was studied. Methods/Procedures: From 44 patients taking clozapine QD or twice daily a total of 319 blood samples were collected at different time points within a dose interval. AGP concentrations were measured in samples drawn just before clozapine intake. A validated liquid chromatography-tandem mass spectrometry method was used for quantification of the (nor)clozapine concentrations. Ultrafiltration was used to separate the bound and unbound molecules. The relation between total concentrations and fractions, and between unbound fractions and AGP concentrations were investigated using linear mixed model analysis. Findings/Results: There was no significant correlation between total clozapine (P = 0.270) and norclozapine (P = 0.678) concentrations and its unbound fractions with total clozapine concentrations up to 1500 μg/ L. A statistically significant (negative) correlation between AGP concentrations and clozapine (P = 0.000) and norclozapine (P = 0.028) unbound fractions was found. Implications/Conclusions: In general, total concentrations remain suitable for therapeutic drug monitoring if clozapine is used once daily. Future research is needed to define if higher total concentrations are warranted in case of lower unbound fractions due to increased AGP concentrations.