The Frequency of CYP2D6 and CYP3A4/5 Genotypes and The Impact of Their Allele Translation and Phenoconversion-Predicted Enzyme Activity on Risperidone Pharmacokinetics in Saudi Children with Autism.

This study looked at how genetic differences affect how children with autism process risperidone medication. Researchers tested 83 Saudi children and found that certain genetic variations influenced how quickly the body breaks down risperidone, but these differences didn't affect the overall medication effectiveness. The findings suggest that other genetic factors, not yet identified, may also play important roles in how children respond to this medication.

This pharmacogenomic study examined 83 Saudi children with autism taking risperidone to understand how genetic variations in CYP2D6 and CYP3A4/5 enzymes affect drug metabolism. Using comprehensive genetic testing, researchers found that CYP2D6 genetic variants significantly influenced risperidone blood levels and metabolism ratios, with different metabolizer phenotypes (intermediate, normal, and ultrarapid) showing distinct pharmacokinetic profiles. However, CYP3A4/5 variants showed no significant impact. Importantly, neither enzyme's genetic variations affected the total active drug levels, suggesting other genetic factors may be involved in risperidone metabolism in this population.

Results suggest CYP2D6 genetic testing may have some utility for risperidone dosing in children with autism, but the lack of impact on total active drug levels questions clinical significance. Further research needed to identify other genetic factors affecting risperidone response before implementing routine pharmacogenomic testing.

Single-center study with moderate sample size (n=83) from one ethnic population. Limited to pharmacokinetic outcomes without clinical effectiveness measures. Cross-sectional design cannot establish causation. Findings may not generalize to other populations.

Data on the role of CYP2D6 and CYP3A4/5 polymorphisms in relation to risperidone (RIS) pharmacokinetics (PK) in children are relatively limited and inconsistent. This is partially attributable to the limited coverage of CYP2D6 and CYP3A4/5 metabolizer phenotypes, particularly those of poor and ultrarapid metabolizers (PMs and UMs), which has led to calls for studies of populations with a non-European background that may carry variants that are less frequent in Europeans. Children ≤ 18 years old with at least 8 weeks of a RIS-based regimen were recruited from three autism centers in Riyadh, Saudi Arabia. The primary outcomes measured were plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) and their dose-adjusted (C/D) ratios as a function of phenotypes and activity score (AS).

For accurate DNA genotyping, targeted pharmacogenomic testing with the Axiom PharmacoFocus Array was performed via examination of a broad collection of probesets targeting CYP2D6 and CYP3A4/5 variants. The frequency of genotypes/phenotypes and the impact of their allele translation and phenoconversion-predicted enzyme activity were examined. The final cohort included 83 individuals. The most common CYP2D6 phenotype in our population was normal metabolizers (NMs, 66.3%).

Inconsistent with some previous studies, the three phenotypes of intermediate metabolizers (IMs), NMs, and UMs were significantly different in terms of RIS concentration, the RIS/9-OH-RIS ratio, the RIS C/D ratio and the 9-OH-RIS C/D ratio. According to AS analyses, there were statistically significant differences in the RIS concentration (P = 0.013), RIS/9-OH-RIS ratio (P < 0.001) and RIS C/D ratio (P = 0.030) when patients were categorized into AS ≤ 1 vs. AS > 1. None of the CYP3A4/5 star allele translated phenotypes revealed a significant influence on any of the RIS PK parameters.

Notably, neither CYP2D6 nor CYP3A4/5 phenotyping demonstrated a significant impact on the total active moiety, suggesting that other gene variants could modulate RIS PK. The study confirmed the previously reported partial impact of the CYP2D6 gene on RIS PK. However, future studies using contemporary genotyping techniques targeting a wide range of variants in other candidate genes must be conducted to further examine their interactive effects on RIS PK and the clinical response.