Gregornik, David

Aims: The primary aim of this study was to determine whether CYP2D6 phenotypes are associated with atomoxetine treatment outcomes in children and adolescents with attention-deficit hyperactivity disorder. Patients and Methods: Patients 21 years and younger with a known CYP2D6 genotype and a prescription for atomoxetine were included in this electronic health record review. The primary outcome was defined as discontinuation of atomoxetine due to a lack of efficacy or due to toxicity. CYP2D6 activity scores were adjusted to account for phenoconversion if patients were concomitantly taking a CYP2D6 inhibitor medication. Results: Of 108 patients that met inclusion criteria, including 13 poor, 30 intermediate, 61 normal, and 4 ultra-rapid CYP2D6 metabolizers after adjusting for phenoconversion. Normal/ultrarapid metabolizers were significantly more likely to discontinue atomoxetine due to lack of efficacy (subdistribution hazard ratio [sHR] = 1.9, p = 0.04), while poor/intermediate metabolizers were significantly more likely to stop due to toxicity (sHR 0.4, p = 0.03). A significant nonlinear effect of adjusted activity score on likelihood of discontinuation due to lack of efficacy ( p < 0.001) or toxicity ( p < 0.001) was identified, where higher CYP2D6 activity scores were associated with more discontinuation due to lack of efficacy and lower activity scores were associated with more discontinuation due to toxicity. When CYP2D6 genotype was available prior to prescribing atomoxetine in intermediate/poor metabolizers, lower median initial doses were observed (0.5 mg/kg/day) compared to those who underwent CYP2D6 genotyping after the initial atomoxetine prescription (0.8 mg/kg/day). Conclusion: Patients with normal or increased CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to a lack of efficacy, while those with reduced function CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to toxicity.

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.