Cytochrome P450 2D6 *17 and *29 Allele Activity for Risperidone Metabolism: Advancing Precision Medicine Health Equity.

CYP2D6 alleles with low frequency in Eurocentrically biased study populations are often excluded from pharmacogenetic investigation and consequently may have misassigned activity values. This health inequity may be contributing to imprecise dose predictions for CYP2D6-metabolizing drugs. The objective of this study was to determine how sub-Saharan African-specific CYP2D6*17 and *29 alleles affect risperidone metabolism. To do this, we generated the largest real-world cohort of risperidone users in an African study population for pharmacogenetic studies. Risperidone users ≤ 18 years old were recruited from the Federal Neuro-Psychiatric Hospital. Health records were obtained by parent report and paper charts. CYP2D6 genotyping was performed for > 20 variants. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined by liquid chromatography mass spectrometry. CYP2D6 activity was calculated based on the metabolic ratio 9-hydroxyrisperidone:risperidone. Multivariable linear regression modeling was performed to determine the association between our alleles of interest and log-transformed ratio-defined CYP2D6 activity relative to star alleles with established activity values. Across 208 enrolled participants, CYP2D6 activity value for *17 was found to be twice that of normal function alleles, while *29 was comparable to no function alleles. These results contrast previous values assigned to *17 and *29 from guidelines, which are not based on evidence with risperidone, suggesting the possibility of substrate specificity for these alleles. Ultimately, our findings have the potential to improve risperidone prescribing, especially for patient groups with substantial sub-Saharan African ancestry. Importantly, this work underscores the critical need to better understand the effects of ancestry-specific alleles for achieving equitable pharmacotherapeutic health outcomes.