Atomoxetine PBPK-PD Clinical Study

Study Overview
=================
Brief Summary
-----------------
The primary aims of this study focus on characterizing the relationship between atomoxetine exposure and clinical outcomes, as assessed by standardized measures. We will also simultaneously monitor side effect of atomoxetine, another measure of clinical outcomes, and categorize study participants on their ability to tolerate atomoxetine.

Detailed Description
-----------------
Atomoxetine (ATX), Strattera®, is a norepinephrine re-uptake transporter inhibitor that is approved by the Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). The drug is often considered a second- or third-line agent, due to the perception that the drug does not work very well. In fact, in a review of studies submitted to the FDA, it reported that there appeared to be discrete classes of response to atomoxetine. After 6-9 weeks of treatment, 47% of the patients were considered responders based on changes in the rating scales used to measure ADHD symptoms whereas 40% of patients were considered non-responders. Statistically significant (p<0.001) differences in scores between responders and non-responders were apparent after the first week of treatment. At the relatively low starting doses of the titration scheme, this suggests that there may be a subgroup of patents who are particularly responsive to ATX. We hypothesize that there could be two reasons for this: 1) variability in drug pharmacokinetics (i.e., inadequate drug concentrations in the blood over time could lead to poor response) and 2) variability in drug pharmacodynamics (i.e. differences at the level of the target of drug action that limit the response to a drug, regardless of concentration of drug present in the blood). The CYP2D6 gene, which encodes for the drug metabolizing enzyme CYP2D6, is responsible for the clearance of ATX from the body, is highly polymorphic. ATX metabolism by CYP2D6 protein is one of the major routes of clearance (i.e., removal) of this drug. Genetic variability in the CYP2D6 gene leads to wide inter-individual variability in the activity of the enzyme, ultimately resulting in differing amount of drug in the body (also referred to as exposure, and is a component of drug pharmacokinetics). Secondly, the SLC6A2 gene which encodes for the norepinephrine reuptake transporter, the drug target for ATX, is also subject to genetic variation. Reported genetic variants of SLC6A2 have been associated with decreased abundance of the transporter. The consequences of SLC6A2 genetic variation with regards to ATX clinical response are currently unknown. In the context of distinct responder and non-responder groups with a population of atomoxetine-treated patients, non-response could be due to definable differences at the level of the drug target (patients unlikely to respond regardless of the ATX concentrations achieved), or simply a consequence of inadequate exposure in a substantial proportion of population. The goal of this study is to address this issue.

Official Title
-----------------
An Open-Label, Single- and Multi-Dose Study to Evaluate the Relationship Between the Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes of Atomoxetine in CYP2D6 Extensive, Intermediate and Poor Metabolizers in Children With Attention Deficit/Hyperactivity Disorder

Conditions
-----------------
ADHD

Intervention / Treatment
-----------------
* Drug: Atomoxetine Hydrochloride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria:• Males and females 6-18 years of age at the time of enrollment Diagnosis of ADHD, as confirmed by a Study Physician at intake visit. Intention of the Study Physician to begin therapy with ATX at intake visit Willing to provide written permission/assent to participate ADHD Medication Status is one of the following: ADHD medication naïve or not currently taking ADHD medication including stimulants, α2-agonists, and ATX, or Currently taking a stimulant for ADHD and is willing to wash out of stimulants prior to starting ATX. This washout is also approved by a Study Physician, or other qualified study personnel (see Section 11.0 for Procedures Involved). Exclusion Criteria: An IQ < 70 A diagnosis of Autism Spectrum Disorder Inability or unwillingness to have blood drawn as described in the protocol schedule of events and consent Underlying risk for cardiotoxicity, such as presentation of structural cardiac abnormalities, cardiomyopathy, or arrhythmias Clinically significant abnormal safety laboratory values as determined by treating physician Diagnosis that may cause abnormal absorption or gastric emptying, such as reflux, inflammatory bowel disease, or Crohn's disease For females, a positive urine pregnancy test Previous history of adverse drug reaction to ATX Use of drugs known to inhibit CYP2D6: Concurrent therapy with sertraline, venlafaxine, imipramine, nortriptyline, quinidine, propafenone, cimetidine, tamoxifen, bupropion, over-the-counter medications containing diphenhydramine, codeine, tramadol, hydrocodone, or oxycodone Concurrent or previous therapy with fluoxetine or paroxetine in the last 2 months Concurrent or previous therapy with terbinafine in the last 6 months Unwillingness or inability to washout of stimulant ADHD medications Concurrent or recent use of other psychiatric/behavioral health drugs including SSRIs, SNRIs, antipsychotics, anxiolytics, anti-epileptics, and α2-agonists that would impact the participant's pharmacokinetic and/or pharmacodynamic baseline Subject is considered by PI to be unsuitable for participation in the study for any reason

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Atomoxetine Hydrochloride|Atomoxetine dose adjusted to achieve pre-defined concentration|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Classified as Responders and Non-responders to Intervention | Classification of participants as responders versus non-responders is based on percent reduction in total National Initiative for Children's Healthcare Quality (NICHQ) Vanderbilt Assessment Scale (3rd edition) score from baseline. Participants with ≥40% reduction in total score from baseline are classified as responders. The scale assesses the presence and severity of 18 DSM-V criteria for attention deficit hyperactivity disorder (ADHD) symptoms. Symptoms are rated on a 4-point Likert-type scale: 0 (Never) to 3 (Very Often). Maximum total symptom score is 54.The measure includes 8 questions assessing functional impairment (Performance). Impairment is rated on a 5-point Likert-type scale: 1 (Excellent) to 5 (Problematic). | 6 weeks | 
| Number of Participants Classified as Responders and Non-responders to Intervention | Classification of participants as responders versus non-responders is based on percent reduction in total National Initiative for Children's Healthcare Quality (NICHQ) Vanderbilt Assessment Scale (3rd edition) score from baseline. Participants with ≥40% reduction in total score from baseline are classified as responders. The scale assesses the presence and severity of 18 DSM-V criteria for attention deficit hyperactivity disorder (ADHD) symptoms. Symptoms are rated on a 4-point Likert-type scale: 0 (Never) to 3 (Very Often). Maximum total symptom score is 54.The measure includes 8 questions assessing functional impairment (Performance). Impairment is rated on a 5-point Likert-type scale: 1 (Excellent) to 5 (Problematic). | 18 weeks | 
| Maximum Plasma Concentration (Cmax) of Atomoxetine | Cmax is the highest concentration of atomoxetine measured over a 12-hour period following administration of the drug on pharmacokinetic study days occurring at baseline (first dose). Cmax is an estimate of atomoxetine systemic exposure and is compared between responders and non-responders. | Baseline (first dose) | 
| Maximum Plasma Concentration (Cmax) of Atomoxetine | Cmax is the highest concentration of atomoxetine measured following administration of the drug on pharmacokinetic study days occurring at 6 weeks. Cmax is an estimate of atomoxetine systemic exposure and is compared between responders and non-responders. | 6 weeks | 
| Maximum Plasma Concentration (Cmax) of Atomoxetine | Cmax is the highest concentration of atomoxetine measured following administration of the drug on pharmacokinetic study days occurring at 18 weeks. Cmax is an estimate of atomoxetine systemic exposure and is compared between responders and non-responders. | 18 weeks | 
| Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | AUC is the area under the plasma concentration-time curve following administration of atomoxetine. For the baseline pharmacokinetic study (first dose of atomoxetine) plasma concentrations were measured at 17 timepoints between 0 and 72 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, and 72 hours) post-dose for CYP2D6 poor and intermediate metabolizers, and 12 timepoints between 0 and 12 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours) after dose administration for all other participants. The AUC was generated using a mixed log-linear approach and extrapolated to infinity. AUC is compared between responders and non-responders. | Baseline (first dose) | 
| Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | For the steady-state pharmacokinetic studies at 6 weeks, plasma concentrations were measured at 15 timepoints between 0 and 24 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours) post-dose for CYP2D6 poor and intermediate metabolizers, and at 12 timepoints between 0 and 12 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours) and extrapolated to 24 hours for all other participants. AUC is compared between responders and non-responders. | 6 weeks | 
| Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | For the steady-state pharmacokinetic studies at 18 weeks, plasma concentrations were measured at 15 timepoints between 0 and 24 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours) post-dose for CYP2D6 poor and intermediate metabolizers, and at 12 timepoints between 0 and 12 hours (0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours) and extrapolated to 24 hours for all other participants. AUC is compared between responders and non-responders. | 18 weeks | 
| Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | DHPG has been proposed as a biomarker of the activity of the norepinephrine reuptake transporter (NET; SLC6A2), the target of atomoxetine action. DHPG is a degradation product of norepinephrine after it has been taken up by pre-synaptic neurons, and higher concentrations in plasma are considered to reflect higher NET activity (higher reuptake of norepinephrine into pre-synaptic neurons). To assess the potential value of DHPG as a biomarker of atomoxetine response in ADHD, absolute baseline and pre-dose concentrations of DHPG will be compared between atomoxetine responders and non-responders. | Baseline | 
| Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | DHPG has been proposed as a biomarker of the activity of the norepinephrine reuptake transporter (NET; SLC6A2), the target of atomoxetine action. DHPG is a degradation product of norepinephrine after it has been taken up by pre-synaptic neurons, and higher concentrations in plasma are considered to reflect higher NET activity (higher reuptake of norepinephrine into pre-synaptic neurons). To assess the potential value of DHPG as a biomarker of atomoxetine response in ADHD, pre-dose concentration of DHPG at the 6-week pharmacokinetic study visit will be compared between atomoxetine responders and non-responders. | 6 weeks | 
| Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | DHPG has been proposed as a biomarker of the activity of the norepinephrine reuptake transporter (NET; SLC6A2), the target of atomoxetine action. DHPG is a degradation product of norepinephrine after it has been taken up by pre-synaptic neurons, and higher concentrations in plasma are considered to reflect higher NET activity (higher reuptake of norepinephrine into pre-synaptic neurons). To assess the potential value of DHPG as a biomarker of atomoxetine response in ADHD, pre-dose concentration of DHPG at the 18-week pharmacokinetic study visit will be compared between atomoxetine responders and non-responders. | 18 weeks | 
| Change in Plasma Concentration of DHPG From Baseline | The change in DHPG will be compared between atomoxetine responders and non-responders. | 6 weeks | 
| Change in Plasma Concentration of DHPG From Baseline | The change in DHPG will be compared between atomoxetine responders and non-responders. | 18 weeks |