ABCB1, ABCG2 and CYP2D6 polymorphism effects on disposition and response to long-acting risperidone

Area of Science:

• Pharmacogenomics
• Neuroscience
• Clinical Pharmacy

Background:

• The impact of multidrug resistance (ABCB1) and breast cancer resistance (ABCG2) gene polymorphisms on long-acting injectable (LAI) risperidone treatment is not well understood.
• Cytochrome P450 (CYP) 2D6 genotype-predicted phenotype is known to affect drug metabolism, but its interaction with transporter polymorphisms in risperidone therapy requires further investigation.

Purpose of the Study:

• To investigate the relationship between ABCB1 and ABCG2 polymorphisms and CYP2D6 genotype-predicted phenotype on risperidone pharmacokinetics and clinical outcomes in schizophrenia patients.
• To determine if these genetic factors influence drug disposition and treatment response to LAI-risperidone.

Main Methods:

• A 24-week observational study involving 101 adult schizophrenia patients initiated on LAI-risperidone.
• Genotyping for CYP2D6, CYP3A4, CYP3A5, ABCG2, and ABCB1 polymorphisms.
• Measurement of steady-state serum levels of risperidone, 9-OH-risperidone, and the active moiety (risperidone + 9-OH-risperidone).
• Assessment of treatment response using the Positive and Negative Syndrome Scale (PANSS) at weeks 12 and 24.

Main Results:

• CYP2D6 normal/ultrarapid metabolizers (NM/UM) showed reduced risperidone and active moiety levels compared to other phenotypes.
• ABCG2 variant allele carriers exhibited pronounced reductions in drug analytes, particularly in CYP2D6 NM/UM subjects.
• ABCB1 polymorphisms did not significantly affect risperidone exposure.
• CYP2D6 NM/UM phenotype was associated with lower odds of PANSS response, while ABCG2 variants increased response odds, and ABCB1 wild-type genotypes decreased response odds.

Conclusions:

• The effect of CYP2D6 phenotype on risperidone systemic exposure is conditional on the ABCG2 421C>A polymorphism.
• ABCG2 and ABCB1 polymorphisms independently influence clinical response to LAI-risperidone, irrespective of drug disposition.