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It is primarily metabolized by CYP2D6 to 9\u2010hydroxyrisperidone, an active metabolite associated with a higher risk of adverse effects. The\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    *\n                    <jats:italic>17<\/jats:italic>\n                    and *\n                    <jats:italic>29<\/jats:italic>\n                    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\u2010European origin. The primary objective of this study is to replicate recently identified risperidone\u2010specific activity for the\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    *\n                    <jats:italic>17<\/jats:italic>\n                    and *\n                    <jats:italic>29<\/jats:italic>\n                    alleles. During psychiatric hospitalization,\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    was genotyped as part of routine care. Remnant plasma specimens were analyzed for risperidone and 9\u2010hydroxyrisperidone by tandem liquid chromatography mass spectrometry in 161 patients administered risperidone. The log\u2010transformed metabolite\u2010to\u2010parent ratio was used to estimate CYP2D6 enzymatic activity. The effect of each\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    allele on activity was assessed with linear regression that included strong CYP2D6 inhibitor use. Patients were predominantly white, non\u2010Hispanic youth, ages 5\u201318\u2009years old (mean 12.5\u2009years), and 26.7% were prescribed concomitant CYP2D6 inhibitors. The frequency of\n                    <jats:italic>*17<\/jats:italic>\n                    and\n                    <jats:italic>*29<\/jats:italic>\n                    alleles were 15.5% and 8.3%, respectively, among Black patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200942). After accounting for CYP2D6 inhibitors in the model, the activity of the *\n                    <jats:italic>17<\/jats:italic>\n                    allele was &gt;\u20094\u2010fold that of the *\n                    <jats:italic>1<\/jats:italic>\n                    allele (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.006) and the *\n                    <jats:italic>29<\/jats:italic>\n                    allele was 10% that of the *\n                    <jats:italic>1<\/jats:italic>\n                    allele (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.021), comparable to alleles with no function. The *\n                    <jats:italic>17<\/jats:italic>\n                    allele confers greater metabolic activity for risperidone than reflected in current pharmacogenetic guidelines. Using existing activity scores may underestimate metabolism in *\n                    <jats:italic>17<\/jats:italic>\n                    carriers and overestimate it in *\n                    <jats:italic>29<\/jats:italic>\n                    carriers. Incorporating substrate\u2010specific activity scores and dosing recommendations would support improved dosing.\n                  <\/jats:p>","DOI":"10.1111\/cts.70525","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:15:41Z","timestamp":1773807341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of\n                    <scp>\n                      <i>CYP2D6<\/i>\n                    <\/scp>\n                    Genotype and Inhibitor Use on Risperidone Metabolism in Children: Functional Insights Into the\n                    <i>*17<\/i>\n                    and\n                    <i>*29<\/i>\n                    Alleles"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3281-3694","authenticated-orcid":false,"given":"Matthew H.","family":"Bennett","sequence":"first","affiliation":[{"name":"Kansas City University  Kansas City Missouri USA"},{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6805-2243","authenticated-orcid":false,"given":"Ethan A.","family":"Poweleit","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9280-1953","authenticated-orcid":false,"given":"Samuel E.","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Division of Child &amp; Adolescent Psychiatry Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0121-0464","authenticated-orcid":false,"given":"Brandon","family":"Retke","sequence":"additional","affiliation":[{"name":"Mass Spectrometry &amp; Bioanalysis Core, Children's Mercy Research Institute, Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Toren","sequence":"additional","affiliation":[{"name":"Mass Spectrometry &amp; Bioanalysis Core, Children's Mercy Research Institute, Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-2641","authenticated-orcid":false,"given":"Jeffrey R.","family":"Strawn","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neuroscience University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6417-3961","authenticated-orcid":false,"given":"Laura B.","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Kansas City  Kansas City Missouri USA"},{"name":"Department of Psychiatry and Behavioral Neuroscience University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Missouri\u2013Kansas City  Kansas City Missouri 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