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

Official title

Clozapine OpTimal Timing for Optimal moNitoring and Side Effects

Overview

The goal of this observational study is to better understand how clozapine treatment can be tailored as regards minimizing side effects and optimizing efficacy and monitoring. Firstly, how clozapine is broken down into norclozapine in the liver and how both clozapine and norclozapine affect side effects are examined. In order to investigate this metabolization process in the liver inflammation levels in the blood are assessed, which inhibit the conversion of clozapine into norclozapine. In addition, various factors related to physical health are assessed, such as blood sugar, cholesterol, weight, waist circumference, blood pressure and heart rate. The role of hormones is investigated, such as cortisol, a stress hormone that affects metabolism and stress levels. Amino acids are examined, which are building blocks of proteins, and specific parts of DNA that influence clozapine metabolism. In addition, investigation follows whether 12 hours after ingestion is a well-chosen time at which the amount of clozapine is measured in the blood in case of ingestion once a day and twice a day. Finally, specific side effects of clozapine are assessed - with special attention to stool - and the severity of the psychiatric symptoms in patients with therapy resistant schizophrenia spectrum disorders.

Detailed description

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.

Primary outcome measures

• Correlation between serum level HbA1c and (nor)clozapine concentrations and ratio. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]

Secondary outcome measures (10)

• Validation of 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. [Time frame: For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.]
• The validity of the current 12-hour post-intake sampling practice. [Time frame: For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.]
• The optimal sampling window for once-daily clozapine therapeutic drug monitoring. [Time frame: For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.]
• The influence of demographic and clinical parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• The correlation of other metabolic and multiple laboratory parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• Correlation between absolute neutrophilic count (ANC) and total white cell count (WCC) and the (nor)clozapine concentrations and ratio. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• Correlation between general side effects of clozapine and the (nor)clozapine concentrations and ratio. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• Correlation between constipation and the (nor)clozapine concentrations and ratio. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• Correlation between symptoms of schizophrenia and the (nor)clozapine concentrations and ratio. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]
• The effect of cortisol concentration and genetics on the correlation of (nor)clozapine concentrations and/or ratio on the metabolic markers. [Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06749041 · COTTONS-v2-22/11/2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗