Nor)Clozapine Kinetics and Side Effects in Therapy Resistant Schizophrenia and the Optimal Sampling Time for Therapeutic Drug Monitoring

Rationale:

Therapeutic drug monitoring (TDM) is essential for clozapine and can enhance therapeutic outcomes and minimize side effects. As of yet, research on (nor)clozapine concentrations and their association to metabolic side effects is limited and inconclusive. Unfortunately, not enough is known about individual risk factors for developing metabolic side effects to personalize clozapine treatment. It would be desirable to have another way to predict which clozapine users are at increased risk of developing severe side effects. Current guidelines are based on limited evidence, potentially resulting in inconsistent or suboptimal monitoring and management.

Objective:

The primary objective is to evaluate the correlation between (nor)clozapine kinetics and serum level HbA1c. Secondary objectives include validating an existing population pharmacokinetic model, assessing the validity of the current 12-hour post-intake sampling practice, determining the optimal sampling window for once-daily clozapine TDM and assessing the correlation of other metabolic and multiple laboratory parameters and influence of demographic and clinical parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine.

Inclusion criteria

• Standard treatment of a stable, oral dose of clozapine for at least one week (at steady state).
• Age between 18-70 years.
• Registered time of intake as well as sampling time and dosage.
• Registered smoking status (yes/no).
• At least two samples in the elimination phase of clozapine with both clozapine and norclozapine measured.
• Measurement of the white cell count at least every three months or more often.
• Routine metabolic screening performed at moment of inclusion.
• Subjects should be able to understand the study information and procedures and give informed consent or when incapacitated subjects are not reliably able to give informed consent their legal representatives should give informed consent under the condition that these subjects are willing to participate.

Exclusion criteria

• Pregnancy.
• Malignancy or treatment with immunosuppressive medication.
• Samples where cessation, start or dose change of interacting co-medication (such as valproic acid, gemfibrozil, fluvoxamine, omeprazole and cyclic oral contraceptives [21 on, 7 days off]) or changes in use of tobacco containing products occurred within seven days prior to blood sampling (21, 28, 34, 35).
• Acute inflammation, infection or samples shortly after intoxication. In case this information is unknown, it may be derived by large unexpected change in levels compared to previous or target levels.
• Not sampled at Starlet (blood collection site) or sampled by dried blood spot
• Unknown status of smoking (including vaping).
• Unknown time of intake of clozapine.
• Unknown time of blood sampling.
• If informed consent is not obtained by the patient or by a legal representative in a mentally incapacitated patient, i.e. a legally incompetent adult.