title: Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC-MS/MS method.
abstract: OBJECTIVE
  Clozapine 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.
  
  
  METHODS
  Serum 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.
  
  
  RESULTS
  For 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.
  
  
  CONCLUSIONS
  This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium. Electronic address: lisbeth.patteet@ua.ac.be.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Patteet
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Kristof E
authors.initials: KE
authors.lastname: Maudens
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Zarha
authors.initials: Z
authors.lastname: Vermeulen
authors.affiliation: Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Dockx
authors.affiliation: Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: De Doncker
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morrens
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Sabbe
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Neels
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001530:Belgium; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003024:Clozapine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012189:Retrospective Studies; D053719:Tandem Mass Spectrometry / Q000379:methods*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine
keywords: Antipsychotic drugs; Clozapine; Therapeutic drug monitoring; UHPLC–MS/MS