Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC–MS/MS method

• 330 serum samples for clozapine monitoring were analyzed using UHPLC–MS/MS.
• Only 22.3% of the clozapine concentrations were found within the therapeutic range.
• 68.2% of the norclozapine concentrations were within the therapeutic range.
• 218 of the 330 serum samples contained, besides clozapine, other antipsychotics.
• This study shows the importance of monitoring clozapine and other antipsychotics.

ObjectiveClozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP–TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography–tandem mass spectrometric method (UHPLC–MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples.Design and methodsSerum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid–liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC–MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP–TDM guidelines.ResultsFor clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350–600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100–600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range.ConclusionThis retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.