Impact of CYP2D6 Genotype and Inhibitor Use on Risperidone Metabolism in Children: Functional Insights Into the *17 and *29 Alleles.

Risperidone, an atypical antipsychotic, is increasingly prescribed in pediatric patients with psychiatric disorders. It is primarily metabolized by CYP2D6 to 9-hydroxyrisperidone, an active metabolite associated with a higher risk of adverse effects. The CYP2D6*17 and *29 alleles are prevalent in individuals of African ancestry and less studied than variants found in European ancestry individuals. This knowledge gap contributes to differences in health outcomes in individuals of non-European origin. The primary objective of this study is to replicate recently identified risperidone-specific activity for the CYP2D6*17 and *29 alleles. During psychiatric hospitalization, CYP2D6 was genotyped as part of routine care. Remnant plasma specimens were analyzed for risperidone and 9-hydroxyrisperidone by tandem liquid chromatography mass spectrometry in 161 patients administered risperidone. The log-transformed metabolite-to-parent ratio was used to estimate CYP2D6 enzymatic activity. The effect of each CYP2D6 allele on activity was assessed with linear regression that included strong CYP2D6 inhibitor use. Patients were predominantly white, non-Hispanic youth, ages 5-18 years old (mean 12.5 years), and 26.7% were prescribed concomitant CYP2D6 inhibitors. The frequency of *17 and *29 alleles were 15.5% and 8.3%, respectively, among Black patients (n = 42). After accounting for CYP2D6 inhibitors in the model, the activity of the *17 allele was > 4-fold that of the *1 allele (p = 0.006) and the *29 allele was 10% that of the *1 allele (p = 0.021), comparable to alleles with no function. The *17 allele confers greater metabolic activity for risperidone than reflected in current pharmacogenetic guidelines. Using existing activity scores may underestimate metabolism in *17 carriers and overestimate it in *29 carriers. Incorporating substrate-specific activity scores and dosing recommendations would support improved dosing.