Monitoring patients using clozapine

Abstract

Clozapine is an antipsychotic drug with distinct therapeutic advantages, including superior efficacy over other antipsychotics in refractory schizophrenia. On the other hand, clozapine is also known for various adverse drug reactions (ADRs) including sialorrhea (30-80%), agranulocytosis (0.8%) and myocarditis (1%). Monitoring by means of laboratory monitoring, including determination of total blood count and therapeutic drug monitoring (TDM), and monitoring of clinical adverse effects is essential for optimization of the benefit-risk balance. In this thesis the following three aspects of monitoring in clozapine therapy were studied: the applicability of FL3-fluorescence as a biomarker to monitor long term adherence to clozapine therapy; the effects of AGP concentration during inflammation on the unbound fraction of clozapine plasma concentrations in patients, contributing to better interpretation of clozapine TDM results; and optimization of recognition and treatment of sialorrhea as an ADRs in patients using clozapine. In a previous study, elevated neutrophil fluorescence – termed FL3-fluoresence – was serendipitously observed in patients using clozapine. In a retrospective cross-sectional study, we confirmed this association and found that FL3-fluorescence increased with increasing clozapine dose. Explorations on the origin of this clozapine associated neutrophil fluorescence revealed that the neutrophil fluorescence was reflected by a 14kDa soluble protein present in azurophilic granules of neutrophils. Consequently, we developed a pharmacokinetic/pharmacodynamic (PK/PD) model relating FL3-fluorescence to clozapine exposure. The model displayed a half-life of FL3-fluorescence of approximately 230 hours. With the developed model and nomogram, clinicians are offered information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Monitoring results need, however, to be put into both patient and clinical context. TDM of clozapine involves measurement of total (unbound plus protein-bound) clozapine plasma concentrations, while the unbound plasma concentrations are responsible for the clinical efficacy and toxicity. A rise in total clozapine plasma concentrations into toxic ranges is seen during inflammation, however this rarely results in clinical toxicity. This may be the result of an increase of the systemic acute phase protein ‘alpha-1-acid glycoprotein’ (AGP) following inflammation. We investigated the association between AGP plasma concentrations and clozapine unbound fraction and found a significant association between elevated AGP plasma concentrations and a lower clozapine unbound fraction. Monitoring and management of bothersome adverse drug reactions (ADRs) including sialorrhea can improve adherence by ameliorating the benefit-risk balance of clozapine from patient perspective. We found that sialorrhea was reported almost four times more often with clozapine use than with use of other antipsychotics and was reported eight times more often by patients than by health-care professionals. Sialorrhea can be managed with off-label treatment including use of anticholinergic agents. In a randomized controlled trial, we showed that the anticholinergic agent glycopyrrolate, dosed two mg once daily, was shown to be a significantly effective anticholinergic agent in the absence of cognitive adverse events. Patient-reported quantification of sialorrhea should be placed into perspective with patients’ perceived burden of sialorrhea and treatment satisfaction. With the research presented in this thesis we have moved a step closer to optimizing treatment with clozapine contributing to rational, effective and safe use of clozapine.