CYP2D6 and Clinical Response to Atomoxetine in Children and Adolescents With ADHD

Michelson, David; Read, Holly A.; Ruff, Dustin; Witcher, Jennifer; Zhang, Shuyu; McCracken, James T.

doi:10.1097/01.chi.0000246056.83791.b6

Cited by 137 publications

(103 citation statements)

References 15 publications

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“…Drug development trials for atomoxetine were notable in that consideration of subjects' CYP2D6 status influenced dosing titration algorithms and subsequently derived approved dosing limits. A recent meta-analysis pooled outcome data from several atomoxetine clinical trials [53]. Poor metabolizers displayed greater symptom improvement than extensive metabolizers, most likely due to higher plasma drug concentration …”

Section: Metabolic Pathways and Pharmacokineticsmentioning

confidence: 99%

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Stein

McGough²

2008

Child and Adolescent Psychiatric Clinics of North America

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SynopsisCurrently, ADHD treatment is often determined empirically through trial and error until an adequate response is obtained or side effects occur. ADHD is highly heritable and there is wide individual variability in response to ADHD medications, suggesting that the mechanism of action of stimulant medications may provide clues for genetic predictors of response. The promise of ADHD pharmacogenetics is far reaching, and includes the potential to develop individualized medication regimens that improve symptom response, decrease risk for side effects, improve long-term tolerability, and thus contribute to long-term treatment compliance and improved general effectiveness. Early ADHD pharmacogenetic studies have focused predominantly on catecholamine pathway genes and response to methylphenidate. Future efforts will also examine a wider range of stimulant and non-stimulant medications on a range of outcome measures and time periods. Based upon these studies, the potential for personalizing ADHD treatment in clinical practice will be determined. IntroductionAttention-Deficit/Hyperactivity Disorder (ADHD) is a common and treatable behavioral syndrome that typically emerges during childhood or adolescence and often persists into adulthood. There are an increasing number of stimulant and non-stimulant medication options for ADHD, with numerous new compounds in development [1]. In acute treatment studies, stimulant medications generally demonstrate large effect sizes on ADHD symptom reduction relative to placebo, with slightly smaller effect sizes in adult studies [2]. Surprisingly, only a minority of children and adolescents with ADHD remain on medication consistently Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. despite persistence of symptoms and impairments. Even among responders, there is marked variability in optimal dosage, duration of effect, and tolerability. Moreover, in spite of acute symptom reduction from ADHD medications, as yet there is little evidence of long-term response and improvement in functioning among those children who received treatment [4,5]. Furthermore, there are few reliable predictors of medication response. In the absence of these data, treatment is often determined "empirically" in clinical practice through a gradual titration of different dosages and trial and error approach to different medications. NIH Public AccessADHD is a highly heritable disorder [6]. The search for candidate genes associated with ADHD has been largely driven by the understanding that medications for the disorder have drug targets in the catecholamine system [7]. Conve...

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Section: Metabolic Pathways and Pharmacokineticsmentioning

confidence: 99%

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Stein

McGough²

2008

Child and Adolescent Psychiatric Clinics of North America

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“…Atomoxetine may be considered a first-line treatment for patients with comorbid anxiety or active substance abuse disorders and is preferred in individuals who suffer from stimulant related side effects such as increased mood lability or tics (Pliszka et al, 2006). One study demonstrated enhanced response in patients identified as cytochrome P 450 2D6 slow metabolizers, presumably due to increased drug plasma levels on standard doses (Michelson et al, 2007). Beyond these narrow instances, clear guidelines for when atomoxetine should be selected for particular patients have remained elusive.…”

Section: Introductionmentioning

confidence: 99%

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: A pilot project

Leuchter¹,

McGough²,

Korb³

et al. 2014

Journal of Psychiatric Research

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b s t r a c tAtomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18e30) enrolled in a multisite, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N ¼ 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD.

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“…ATX biotransformation by pediatric HLMS was conducted at three concentrations of ATX that reflected systemic plasma drug levels, bracketing an inferred target C max of 3 mM (Kratochvil et al, 2007;Michelson et al, 2007). Concentration-dependent metabolite formation was observed for all metabolites analyzed, and the results are shown in Table 2, Supplemental Tables 2 and 3.…”

Section: Resultsmentioning

confidence: 98%

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children

Dinh

Pearce

Haandel

et al. 2016

Drug Metabolism and Disposition

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Atomoxetine (ATX) is a second-line nonstimulant medication used to control symptoms of attention deficit hyperactivity disorder (ADHD). Inconsistent therapeutic efficacy has been reported with ATX, which may be related to variable CYP2D6-mediated drug clearance. We characterized ATX metabolism in a panel of human liver samples as a basis for a bottom-up PBPK model to aid in ATX exposure prediction and control. K m , V max , and Cl int values in pooled human liver microsomes (HLMs) were 2.4 mM, 479 pmol/min/mg protein, and 202 ml/min/mg protein, respectively. Mean population values of kinetic parameters are not adequate to describe variability in a population, given that K m , V max , and Cl int values from single-donor HLMs ranged from 0.93 to 79.2 mM, 20.0 to 1600 pmol/min/mg protein, and 0.3 to 936 ml/min/mg protein. All kinetic parameters were calculated from 4-hydroxyatomoxetine (4-OH-ATX) formation. CYP2E1 and CYP3A contributed to 4-OH-ATX formation in livers with CYP2D6 intermediate and poor metabolizer status. In HLMs with lower CYP2D6 activity levels, 2-hydroxymethylatomoxetine (2-CH 2 OH-ATX) formation became a more predominant pathway of metabolism, which appeared to be catalyzed by CYP2B6. ATX biotransformation at clinically relevant plasma concentrations was characterized in a panel of pediatric HLM (n = 116) samples by evaluating primary metabolites. Competing pathways of ATX metabolism [N-desmethylatomoxetine (NDM-ATX) and 2-CH 2 OH-ATX formation] had increasing importance in livers with lesser CYP2D6 activity, but, overall ATX clearance was still compromised. Modeling ATX exposure to individualize therapy would require comprehensive knowledge of factors that affect CYP2D6 activity as well as an understanding of competing pathways, particularly for individuals with lower CYP2D6 activity.

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CYP2D6 and Clinical Response to Atomoxetine in Children and Adolescents With ADHD

Cited by 137 publications

References 15 publications

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: A pilot project

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children

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