Saliva Based Clozapine Therapeutic Drug Monitoring: A Systematic Review

Clozapine is superior in the treatment of treatment-refractory schizophrenia but requires therapeutic drug monitoring (TDM) due to its unpredictable pharmacokinetics and dose-dependent side effects. This systematic review evaluates saliva as a more patient-friendly sampling strategy for clozapine TDM. A systematic search was carried out using MEDLINE, Embase, APA PsycInfo, and Cochrane Central Register of Controlled Trials (CCTR) through Ovid. Studies were eligible for inclusion if data on clozapine pharmacokinetics in saliva were described. To assess the feasibility of saliva for the TDM of clozapine, ease of saliva collection, method of detection, detectability of clozapine in saliva, correlation of clozapine concentrations in saliva compared to blood, clozapine stability in saliva, and clinical validation were taken into account. A total of nine studies were included. Overall, the collection of saliva was considered simple, less invasive, and quick compared to the collection of blood. Clozapine was found stable for up to 6 months when stored at -20°C. Various methods were used for the detection of clozapine with a lower limit of detection (LLOQ) ranging from 0.1 to 15 ng/mL. Clozapine saliva concentrations between 8.50 ng/mL and 2,720 ng/mL were observed, and no correlation between clozapine levels in saliva and blood was found. Although saliva is a promising specimen for the TDM of clozapine, no clear recommendation could be made to replace blood with saliva due to methodological issues with the included studies. For this reason, further clinical validation studies are needed.