The Association Between Clozapine Plasma Concentration, CYP2D6 (*10, *2) Polymorphisms and Risk of Adverse Reactions

Area of Science:

• Pharmacogenetics
• Clinical Chemistry
• Psychiatry

Background:

• Clozapine is an essential antipsychotic for treating schizophrenia.
• Adverse reactions and varying plasma concentrations of clozapine present clinical challenges.
• Cytochrome P450 2D6 (CYP2D6) genetic polymorphisms are known to affect drug metabolism.

Purpose of the Study:

• To investigate the association between CYP2D6 genetic polymorphisms (rs1065852 [*10] and rs16947 [*2]) and clozapine plasma concentrations.
• To explore the relationship between clozapine levels, CYP2D6 genotypes, and the risk of adverse reactions.
• To establish a therapeutic reference range for clozapine in Chinese schizophrenia patients.

Main Methods:

• 100 Chinese inpatients with schizophrenia had their steady-state clozapine plasma concentrations measured using 2-dimensional liquid chromatography.
• CYP2D6 [*10] and [*2] polymorphisms were identified using fluorescent in situ hybridization.
• Adverse reactions, including changes in white blood cells, neutrophils, creatine kinase, alanine aminotransferase, and aspartate transferase, were monitored over 6 months.

Main Results:

• Significant linear associations were found between clozapine plasma concentration and decreased white blood cell/neutrophil counts and elevated liver enzymes.
• Patients with CYP2D6 *10TT and *2CC genotypes exhibited the highest clozapine plasma concentrations (P < .05).
• Adverse reactions were significantly more pronounced in patients with *10TT and *2CC genotypes compared to other genotypes (P < .05).

Conclusions:

• CYP2D6 genotyping and therapeutic drug monitoring of clozapine are valuable tools.
• These methods can aid in identifying schizophrenia patients at higher risk for clozapine-induced adverse reactions.
• A therapeutic reference range of 102.5-483.1 ng/mL for clozapine in Chinese patients was defined.