The significance of sampling time in therapeutic drug monitoring of clozapine

• Published in: Acta psychiatrica Scandinavica Vol. 135; no. 2; pp. 159 - 169
• Main Authors: Jakobsen, M. I., Larsen, J. R., Svensson, C. K., Johansen, S. S., Linnet, K., Nielsen, J., Fink‐Jensen, A.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-02-2017
• Subjects: Adult; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; clozapine; Clozapine - administration & dosage; Clozapine - analogs & derivatives; Clozapine - blood; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Humans; Male; Middle Aged; norclozapine; Psychiatry; Psychopharmacology; Psychotropic drugs; sampling time; Schizophrenia - blood; Schizophrenia - drug therapy; serum concentration; therapeutic drug monitoring; Young Adult; serum concentration; clozapine; norclozapine; therapeutic drug monitoring; sampling time
• ISSN: 0001-690X; 1600-0447
• DOI: 10.1111/acps.12673

Objective
Therapeutic drug monitoring (TDM) of clozapine is standardized to 12‐h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s‐) of clozapine and its metabolite N‐desmethyl‐clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose.
Method
Forty‐six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10–14 h postdose.
Results
Minor changes in median percentage values were observed for both s‐clozapine (−8.4%) and s‐norclozapine (+1.2%) across the 4‐h time span. Maximum individual differences were 42.8% for s‐clozapine and 38.4% for s‐norclozapine. Compared to 12‐h values, maximum median differences were 8.4% for s‐clozapine and 7.3% for s‐norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s‐clozapine and 105.0% for s‐norclozapine. The magnitude of s‐clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis.
Conclusion
The impact of deviations in clozapine TDM sampling time, within the time span of 10–14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.