Jacob Tyler Brown

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.

Objective: Our primary objective is to demonstrate the benefits of pharmacogenomic (PGx) education for pharmacists that serve rural and underserved communities through pre- and post-surveys assessing their overall change in knowledge and attitudes towards PGx testing. Methods: Participants completed a 16-week, asynchronous didactic course, attended in-person case-based PGx presentations from content experts, and viewed materials from a two-day international PGx conference. Pre- and post-surveys designed to measure changes in self-assessed knowledge, confidence, and attitudes towards PGx testing were completed by all participants. All participants who had completed the program were also invited to take a longitudinal survey to assess long-term program impacts. Results: Twenty-three participants located throughout the state of Minnesota completed the program. Participant’s confidence in their PGx knowledge increased significantly from the beginning of the program to the end. In the longitudinal survey, nearly all participants (93%) responded “yes” when asked if the program influenced their perspectives on the importance of PGx in pharmacy and healthcare, and nearly 75% responded “yes” when asked if the PGx certificate program had contributed to their professional growth or career advancement. The majority (87%) reported that they had shared the knowledge gained from the program with other healthcare providers. Conclusion: These findings show a high level of impact on PGx knowledge in pharmacists practicing in rural and underserved areas, and highlight increased likelihood of PGx implementation after the education program.

Serotonin-related adverse drug reactions (ADRs) of selective serotonin reuptake inhibitors, including serotonin toxicity (ST) and antidepressant discontinuation syndrome (ADS), may significantly affect adherence to antidepressant therapy. ST is a rare but potentially serious adverse drug reaction resulting from excessive serotonergic activity, while ADS may occur after the abrupt discontinuation or dose reduction of an antidepressant. Both complications may be influenced by pharmacokinetic and pharmacogenetic (PGx) factors, although research on these relationships is limited. This case report describes a 40-year-old, medically healthy patient identified to be a CYP2C19 *2/*2 poor metabolizer (PM) who potentially experienced ST and prolonged ADS following treatment with escitalopram. After starting escitalopram while on buspirone and stimulant medications, she developed symptoms consistent with ST, including agitation, confusion, diarrhea, and muscle rigidity, leading to discontinuation. A retrial of escitalopram after 3 weeks resulted in similar symptoms. Despite ongoing ST-like symptoms, the patient chooses to continue escitalopram for 2 years, given her perceived benefits with treatment. Upon discontinuation after being on escitalopram for more than 2 years, the patient experienced prolonged withdrawal symptoms consistent with ADS. This case highlights the utility of pre-emptive PGx testing in antidepressant therapy and the importance of interprofessional care in enhancing the patient’s self-efficacy.

Pharmacogenomic (PGx) considerations are increasingly influencing health system formularies, prompting Pharmacy and Therapeutics (P&T) committees to integrate genetic insights into their decision‐making processes. This can be the case in several clinical scenarios, including (1) Prioritizing the use of lower‐cost drugs, where PGx testing is applied to guide the use of lower‐cost medications when appropriate, (2) Rescuing medications that are effective in the majority of individuals but were removed from the formulary because of harm in a subset of individuals with a specific phenotype, (3) Improving medication safety by utilizing PGx testing/results to guide initiation of reduced drug doses or use of alternative therapy in patients with at‐risk genotypes, and (4) Restricting use of high‐cost drugs to individuals most likely to respond based on genotype. The primary objective of this PRN opinion piece is to describe how PGx impacts formulary management, including the challenges and opportunities that arise from precision medicine approaches to prescribing.

Atomoxetine (ATX) is a non‐stimulant used to treat attention‐deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4‐hydroxyatomoxetine (4‐OH); N ‐desmethylatomoxetine (NDA); and 2‐carboxymethylatomoxetine (2‐COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed‐effect modeling approach was used to analyze ATX, 4‐OH, and NDA plasma and urine, and 2‐COOH urine profiles obtained over 24–72 hours from children with ADHD ( n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4‐OH, and NDA in plasma and urine, and 2‐COOH in urine was developed. Plasma ATX, 4‐OH, and NDA were modeled using two‐compartment models with first‐order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4‐OH, and systemic exposure of NDA. CL/F of ATX varied almost 7‐fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4‐OH, and NDA plasma and urine, and 2‐COOH urine profiles. Application of the model shows the potential for AS‐based dosing recommendations for improved individualized dosing.

Inspiring Inquiry and Improvement in Pharmacy Practice, Education, and Policy A quarterly publication featuring case studies, clinical experiences, commentaries, idea papers, original research, and review articles that focus on the leading edge, novel ideas for improving, modernizing, and advancing pharmacy practice, education, and policy. INNOVATIONS in pharmacy is an academic, peer reviewed, open-access journal. Sponsored by U of MN College of Pharmacy Inspiring Inquiry and Improvement in Pharmacy Practice, Education, and Policy. A quarterly publication featuring case studies, clinical experiences, commentaries, idea papers, original research, review articles, and student projects that focus on leading edge, novel ideas for improving, modernizing, and advancing pharmacy practice, education, and policy. INNOVATIONS in pharmacy.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI‐like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin‐2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Background: Methylphenidate is the most prescribed stimulant to treat attention deficit-hyperactivity disorder (ADHD). Despite its widespread usage, a fair proportion of children are classified as non-responders to the medication. Variability in response and occurrence of adverse events with methylphenidate use may be due to several factors, including drug-drug interactions as well as pharmacogenetic differences resulting in pharmacokinetic and/or pharmacodynamic variances within the general population. The objective of this study was to analyze the effect of carboxylesterase 1 (CES1) variants on the frequency of adverse effects and dosing requirements of methylphenidate in children with ADHD.Methods: This was a retrospective cohort study of children and adolescents who met the inclusion criteria and had a routine visit during the enrollment period were invited to participate. Inclusion criteria included: ADHD diagnosis by a healthcare provider, between 6 and 16 years of age at the time of permission/assent, had not previously been prescribed methylphenidate, and treatment with any methylphenidate formulation for at least three consecutive months. Three months of records were reviewed in order to assess changes in dose and frequency of discontinuing methylphenidate. Participants’ ADHD symptoms, medication response, adverse effects, select vitals, and dose were extracted from the electronic health record. Saliva samples were collected by trained study coordinators. Haplotypes were assigned based on copy number in different portions of the CES1 gene. Due to limited numbers, diplotypes (combinations of two haplotypes) were grouped for analysis as CES1A1/CES1A1, CES1A1/CES1A1c and CES1A1c/CES1A1c.Results: A total of 99 participants (n = 30 female; n = 69 male) had both clinical data and CES1 sequencing data, with an average age of 7.7 years old (range 3–15 years). The final weight-based dose in all individuals was 0.79 mg/kg/day. The most common adverse effects reported were decreased appetite (n = 47), weight loss (n = 24), and sleep problems (n = 19). The mean final weight-based dose by haplotype was 0.92 mg/kg for CES1A2/CES1A2, 0.81 mg/kg for CES1A2/CES1P1, and 0.78 mg/kg for CES1P1/CES1P1. After correction for multiple hypothesis testing, only one SNV, rs114119971, was significantly associated with weight-based dosing in two individuals. The individuals with the rs114119971 SNV had a significantly lower weight-based dose (0.42 mg/kg) as compared to those without (0.88 mg/kg; p < 0.001).Discussion: Variation in CES1 activity may impact dose requirements in children who are prescribed methylphenidate, as well as other CES1 substrates. Although intriguing, this study is limited by the retrospective nature and relatively small sample size.

Introduction: While pharmacogenomic (PGx) testing is routine in urban healthcare institutions or academic health centers with access to existing expertise, uptake in medically-underserved areas is lagging. The primary objective of this workforce education program is to extend access to didactic, case-based and clinical PGx training for pharmacists serving rural Minnesota and populations experiencing health disparities in Minnesota.Methods: A PGx workforce training program funded through the Minnesota Department of Health was offered through the University of Minnesota College of Pharmacy (COP) to pharmacists working in rural and/or underserved areas in the state of Minnesota. Learning activities included a 16-week, asynchronous PGx didactic course covering PGx topics, a 15-min recorded presentation, an in-person PGx case-based workshop, and a live international PGx Conference hosted by the University of Minnesota COP and attendance at our PGx Extension of Community Health Outcomes (ECHO).Results: Twenty-nine pharmacists applied for the initial year of the program, with 12 (41%) being accepted. Four (33%) practiced in a hospital setting, four (33%) in retail pharmacy, two (17%) in managed care, and two (17%) in other areas. The majority had not implemented a PGx program as part of their practice, although nearly all responded definitely or probably yes when asked if they expected their organization to increase its use of PGx testing services over the next three years. All participants either strongly or somewhat agreed that this program helped them identify how and where to access clinical PGx guidelines and literature and improved their ability to read and interpret PGx test results. Eight participants (67%) strongly or somewhat agreed that they expected to increase the number of PGx consultations in their practice, while ten (83%) strongly or somewhat agreed they would be able to apply what they learned in this program to their practice in the next six months to a year.Discussion: This novel PGx training program focused exclusively on pharmacists in rural and/or underserved areas with a delivery method that could be accomplished conveniently and remotely. Although most participants’ organizations had yet to implement PGx testing routinely, most anticipated this to change in the next few years.

Background: Sertraline is commonly prescribed to children for the treatment of anxiety and major depressive disorder and is metabolized in part by CYP2C19. While dosing recommendations based on CYP2C19 genotype exist, there is sparse data in children on the relationship between sertraline concentrations and CYP2C19 genotype. Additionally, although rarely utilized in the United States, therapeutic drug monitoring can also help to guide dosing. The primary objective of this pilot study was to compare sertraline concentrations with CYP2C19 genotype. Secondary objectives included exploring the feasibility of using pharmacogenetic testing and therapeutic drug monitoring in a residential treatment center for children and adolescents. Methods: This study was a prospective, open-label study of children prescribed sertraline being treated at a residential treatment center for children and adolescents. Individuals were included if they were < 18 years of age, taking sertraline for at least 2 weeks allowing them to reach steady-state concentrations, being treated through the residential treatment program, and able to understand and speak English. Results: A total of 20 participants (80% female) completed all study procedures, including pharmacogenetic testing and therapeutic drug monitoring, with an average age of 15.4 years (range: 9-17 years). Forty percent (n=8) of participants had a diagnosis of Generalized Anxiety Disorder, while 30% (n=6) had a diagnosis of Major Depressive Disorder. Overall, average sertraline and desmethylsertraline concentrations were 21.1 ng/ml (range: 1-78 ng/ml) and 52.4 ng/ml (range: 1-258 n/ml). Based on CYP2C19 genotypes, 60% (n=12) were normal metabolizers, 10% (n=2) were intermediate metabolizers, and 30% (n=6) were rapid metabolizers. Daily sertraline dose (mg/day) accounted for a significant amount of the observed variability in sertraline (p2=0.62) and desmethylsertraline concentrations (p2=0.45). When comparing weight-based dosing by sertraline and desmethylsertraline concentrations, sertraline daily dose by weight (mg/kg/day) also accounted for a significant amount of the observed variability in sertraline (p2=0.60) and desmethylsertraline (p2=0.59) concentrations. Average daily and weight-based doses for CYP2C19 intermediate, normal, and rapid metabolizers were 75 mg/day, 87.5 mg/day, and 79.2 mg/day and 1.5 mg/kg/day, 1.3 mg/kg/day, and 1.1 mg/kg/day, though these were not significantly different. Conclusion: This small, pilot study showed sertraline dose to be significantly associated with sertraline and desmethylsertraline concentrations. No differences were noted between CYP2C19 metabolizer groups, likely due to the limited sample size. These results also suggest that ordering pharmacogenetic testing and therapeutic drug monitoring in the setting of a child and adolescent residential treatment center is feasible.