Clinical and Genetic Influencing Factors on Clozapine Pharmacokinetics

Study Overview
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Brief Summary
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Clozapine (Clz), an atypical antipsychotic, is the reference medication for patients with treatment-resistant schizophrenia. Due to the high inter-individual variability of its pharmacokinetics and its narrow therapeutic index, a close therapeutic drug monitoring (TDM) of Clz is highly recommended. Several factors can cause a variation in the pharmacokinetics as age, smoking habits, coffee consumption and drug interaction. Genetic factors related to hepatic expression levels of the cytochrome P450 (CYP), regulate the hepatic clearance of Clz, thereby determine its bioavailability. The CYP1A2 and CYP2C19 isoenzymes are mainly responsible for the metabolism of several drugs including Clz. It has been demonstrated that there is an interethnic variation in the expression and function of these two isoenzymes. This variation is caused by single nucleotide polymorphisms (SNPs) of genes encoding these proteins. While the Influence of the different polymorphisms related to CYP1A2 and CYP2C19 have been established especially in Asian and Caucasian populations, no study has examined the impact of these SNPs in the southern Mediterranean populations. Moreover, the impact of these SNPs is very controversial. The present study aims to investigate in Tunisian schizophrenic patients, the influence of genetic (CYP1A2 and CYP2C19 polymorphisms) and non-genetic factors on Clz pharmacokinetics.

Official Title
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Clinical and Genetic Influencing Factors on Clozapine Pharmacokinetics in Schizophrenic Patients

Conditions
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CYP1A2 Polymorphism, CYP2C19 Polymorphism, Clozapine, Schizophrenia

Intervention / Treatment
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* Other: Determination of plasma concentration of clozapine/ Genotyping


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Schizophrenic patients receiving clozapine Good adherence to the treatment (clozapine) Exclusion Criteria: Patients who were co-prescribed drugs that affected the pharmacokinetics of Clozapine. Patients who presented gastrointestinal disorders disturbing absorption of clozapine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Schizophrenic patients<br>Determination of trough plasma concentration of clozapine (C0) Genotyping of CYP1A2 & CYP2C19 Drug: Leponex (Clozapine) : was started at a dose of 25 mg/j, the dose was gradually increased and was administered in one, two or three divided doses. | Other: Determination of plasma concentration of clozapine/ Genotyping<br>* Determination of trough plasma concentration of clozapine (C0) Genotyping of CYP1A2 & CYP2C19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of trough plasma concentration of clozapine (C0) | Technique : HPLC/UV (high-performance liquid chromatography associated with a UV detector) | One and a half months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the correlation between the presence of CYP1A2*1F (rs762551;-163C> A), CYP1A2*1C (rs2069514;-3860 G> A) and CYP 2C19*2 (rs4244285; 681G>A) and the variability of C0/Daily dose. | - Technique: PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) | One and a half months |