Risperidone Pharmacogenetics: The Impact of Star Alleles' Predicted Phenotypes on Global Safety in Autistic Children

Abstract

Background and Objective: The incidence of risperidone (RIS)-induced adverse events (AEs) exhibits wide interindividual variability among children and with respect to different ethnogeographic backgrounds. Evidence on the association between certain gene polymorphisms and the risk of developing AEs in children is limited. The specific objectives of the current study of Saudi children with autism spectrum disorder (ASD) included examining the association of CYP450 genetic predictors (specifically, the predicted phenotypes of CYP2D6 and CYP3A4/5 star alleles) with global safety scores and specific AEs. Materials and Methods: The final cohort included 89 children. The AEs were rated by validated assessments (UKU and MSAS). The DNA genotyping was performed via examination of a broad collection of probesets targeting CYP2D6 and CYP3A4/5 variants among the "actionable" pharmacogenetic testing (PGx) in the Axiom Pharmaco Focus Array. Individual genotype calls were grouped into various phenotypes, including ultrarapid metabolizers (UMs), extensive or normal metabolizers (NMs), intermediate metabolizers (IMs), or poor metabolizers (PMs). Results: A total of 64% of included children (n = 57) had at least one AE according to the UKU scale and 37.1% of the AEs were severe. Based on the MSAS scale, 28 children (31.5%) experienced at least one extrapyramidal symptoms (EPS). The adjusted analyses revealed a statistically non-significant impact of CYP2D6 and CYP3A4 phenotypes on global scores of the UKU scale. However, RIS plasma levels and not its metabolite, were significantly associated with increased MSAS severity, suggesting that CYP2D6 IMs are more likely to have clinically significant EPSs than NMs or UMs (p-values of NMs vs IMs = 0.017 and UMs vs IMs = 0.021). Conclusion: The current investigation demonstrated that CYP450 PGx has limited utility for predicting the global severity of RIS-induced AEs in children and highlighted the need for simultaneous genotyping of potential pharmacodynamic markers to better explain the interindividual variability in AE subtypes.