PMID- 38375040 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240221 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 15 DP - 2024 TI - Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism. PG - 1356763 LID - 10.3389/fphar.2024.1356763 [doi] LID - 1356763 AB - Background: Autism spectrum disorders (ASDs) encompass a broad range of phenotypes characterized by diverse neurological alterations. Genomic studies have revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and genes involved in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of antipsychotic drugs employed in ASD management. Given the conflicting data originating from candidate PK or PD gene association studies in diverse ethnogeographic ASD populations, dosage individualization based on "actionable" pharmacogenetic (PGx) markers has limited application in clinical practice. Additionally, off-label use of different antipsychotics is an ongoing practice, which is justified given the shortage of approved cures, despite the lack of satisfactory evidence for its safety according to precision medicine. This exploratory study aimed to identify PGx markers predictive of risperidone (RIS) exposure in autistic Saudi children. Methods: This prospective cohort study enrolled 89 Saudi children with ASD treated with RIS-based antipsychotic therapy. Plasma levels of RIS and 9-OH-RIS were measured using a liquid chromatography-tandem mass spectrometry system. To enable focused exploratory testing, genotyping was performed with the Axiom PharmacoFocus Array, which included a collection of probe sets targeting PK/PD genes. A total of 720 PGx markers were included in the association analysis. Results: A total of 27 PGx variants were found to have a prominent impact on various RIS PK parameters; most were not located within the genes involved in the classical RIS PK pathway. Specifically, 8 markers in 7 genes were identified as the PGx markers with the strongest impact on RIS levels (p < 0.01). Four PGx variants in 3 genes were strongly associated with 9-OH-RIS levels, while 5 markers in 5 different genes explained the interindividual variability in the total active moiety. Notably, 6 CYP2D6 variants exhibited strong linkage disequilibrium; however, they significantly influenced only the metabolic ratio and had no considerable effects on the individual estimates of RIS, 9-OH-RIS, or the total active moiety. After correction for multiple testing, rs78998153 in UGT2B17 (which is highly expressed in the brain) remained the most significant PGx marker positively adjusting the metabolic ratio. For the first time, certain human leukocyte antigen (HLA) markers were found to enhance various RIS exposure parameters, which reinforces the gut-brain axis theory of ASD etiology and its suggested inflammatory impacts on drug bioavailability through modulation of the brain, gastrointestinal tract and/or hepatic expression of metabolizing enzymes and transporters. Conclusion: Our hypothesis-generating approach identified a broad spectrum of PGx markers that interactively influence RIS exposure in ASD children, which indicated the need for further validation in population PK modeling studies to define polygenic scores for antipsychotic efficacy and safety, which could facilitate personalized therapeutic decision-making in this complex neurodevelopmental condition. CI - Copyright (c) 2024 Shilbayeh, Adeen, Ghanem, Aljurayb, Aldilaijan, AlDosari and Fadda. FAU - Shilbayeh, Sireen Abdul Rahim AU - Shilbayeh SAR AD - Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. FAU - Adeen, Iman Sharaf AU - Adeen IS AD - Department of Pediatric Behavior and Development and Adolescent Medicine, King Fahad Medical City, Riyadh, Saudi Arabia. FAU - Ghanem, Ezzeldeen Hasan AU - Ghanem EH AD - Pharmaceutical Analysis Section, King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia. FAU - Aljurayb, Haya AU - Aljurayb H AD - Molecular Pathology Laboratory, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia. FAU - Aldilaijan, Khawlah Essa AU - Aldilaijan KE AD - Health Sciences Research Center, King Abdullah Bin Abdulaziz University Hospital, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. FAU - AlDosari, Fatimah AU - AlDosari F AD - Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Jeddah, Saudi Arabia. FAU - Fadda, Abeer AU - Fadda A AD - Independent researcher, Malaga, Spain. LA - eng PT - Journal Article DEP - 20240205 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC10875102 OTO - NOTNLM OT - array genotyping OT - autism OT - exploratory OT - pharmacogenetic testing OT - risperidone pharmacokinetics COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/02/20 11:51 MHDA- 2024/02/20 11:52 PMCR- 2024/02/05 CRDT- 2024/02/20 03:38 PHST- 2023/12/16 00:00 [received] PHST- 2024/01/24 00:00 [accepted] PHST- 2024/02/20 11:52 [medline] PHST- 2024/02/20 11:51 [pubmed] PHST- 2024/02/20 03:38 [entrez] PHST- 2024/02/05 00:00 [pmc-release] AID - 1356763 [pii] AID - 10.3389/fphar.2024.1356763 [doi] PST - epublish SO - Front Pharmacol. 2024 Feb 5;15:1356763. doi: 10.3389/fphar.2024.1356763. eCollection 2024.