ADHD
Conditions
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.
Interventions
DRUGAtomoxetine Hydrochloride
Atomoxetine dose adjusted to achieve pre-defined concentration
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Mercy Hospital Kansas City
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Classified as Responders and Non-responders to Intervention | 6 weeks | 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). |
| Maximum Plasma Concentration (Cmax) of Atomoxetine | Baseline (first dose) | 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. |
| Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Baseline (first dose) | 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. |
| Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Baseline | 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. |
| Change in Plasma Concentration of DHPG From Baseline | 6 weeks | The change in DHPG will be compared between atomoxetine responders and non-responders. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited over 6 years from a patient population seeking care for Attention Deficit Hyperactivity Disorder (ADHD).
Pre-assignment details
A total of 51 participants were enrolled in the study. All participants completed a screening visit, and 9 participants screenfailed/were determined to be ineligible.
Participants by arm
| Arm | Count |
|---|---|
| Atomoxetine HCl (Strattera) Study participants will receive atomoxetine at a dose expected to result in steady-state maximum concentration (Cmax,ss) values of 400 ng/mL. Individualized dose to achieve the desired Cmax,ss of 400 ng/ml (approximately 90 minutes after dose administration) is determined using a pharmacokinetic model that includes as input information each participant's CYP2D6 genotype-predicted phenotype, height, weight, body habitus, and gender. Study clinicians may titrate up the dose to reach predicted Cmax,ss values of 600 ng/mL or 800 ng/mL according to participant response. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disruption of study due to COVID-19 | 4 |
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Protocol Violation | 4 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Atomoxetine HCl (Strattera) |
|---|---|
| ADHD Subtype (based on K-SADS-PL) Below Threshold | 2 Participants |
| ADHD Subtype (based on K-SADS-PL) Combine Subtype | 21 Participants |
| ADHD Subtype (based on K-SADS-PL) Hyperactive/Impulsive Subtype | 3 Participants |
| ADHD Subtype (based on K-SADS-PL) Inattentive Subtype | 16 Participants |
| ADHD Subtype (based on NICHQ Vanderbilt Assessment Scale score) Below Threshold | 4 Participants |
| ADHD Subtype (based on NICHQ Vanderbilt Assessment Scale score) Combined Subtype | 27 Participants |
| ADHD Subtype (based on NICHQ Vanderbilt Assessment Scale score) Hyperactive/Impulsive Subtype | 2 Participants |
| ADHD Subtype (based on NICHQ Vanderbilt Assessment Scale score) Inattentive Subtype | 9 Participants |
| Age, Continuous | 10.62 years STANDARD_DEVIATION 2.75 |
| CYP2D6 Activity Score 0 | 3 Participants |
| CYP2D6 Activity Score 0.25 | 3 Participants |
| CYP2D6 Activity Score 0.5 | 1 Participants |
| CYP2D6 Activity Score 0.75 | 1 Participants |
| CYP2D6 Activity Score 1 | 15 Participants |
| CYP2D6 Activity Score 1.25 | 6 Participants |
| CYP2D6 Activity Score 1.5 | 5 Participants |
| CYP2D6 Activity Score 2 | 7 Participants |
| CYP2D6 Activity Score 3 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Neuropsychiatric Comorbidities Anxiety | 3 Participants |
| Neuropsychiatric Comorbidities Dyslexia | 2 Participants |
| Neuropsychiatric Comorbidities Learning Delay | 2 Participants |
| Neuropsychiatric Comorbidities None | 29 Participants |
| Neuropsychiatric Comorbidities Oppositional Defiant Disorder | 4 Participants |
| Neuropsychiatric Comorbidities Other | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 36 Participants |
| Weight | 42.93 kilograms (kg) STANDARD_DEVIATION 20.78 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 42 |
| other Total, other adverse events | 37 / 42 |
| serious Total, serious adverse events | 0 / 42 |
Outcome results
Primary
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.
Time frame: Baseline (first dose)
Population: 6-week and 18-week responder classifications have different sample sizes, as there are 2 milestones within this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Responder at 6 weeks | 1515.3 (ng*hours)/mL | Standard Deviation 1169.2 |
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Non-responder at 6 weeks | 1246.9 (ng*hours)/mL | Standard Deviation 913.4 |
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Responder at 18 weeks | 1495.7 (ng*hours)/mL | Standard Deviation 1197.6 |
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Non-responder at 18 weeks | 1462.7 (ng*hours)/mL | Standard Deviation 1283.4 |
Comparison: Comparing 6-week responders and 6-week non-respondersp-value: 0.495t-test, 2 sided
Comparison: Comparing 18-week responders and 18-week non-respondersp-value: 0.955t-test, 2 sided
Primary
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.
Time frame: 18 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Responders | 3149.2 (ng*hours)/mL | Standard Error 511.3 |
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Non-Responders | 2880.0 (ng*hours)/mL | Standard Error 696.7 |
p-value: 0.759t-test, 2 sided
Primary
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.
Time frame: 6 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Responders | 2802.5 (ng*hours)/mL | Standard Error 423.4 |
| Atomoxetine HCl (Strattera) | Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine | Non-Responders | 2809.4 (ng*hours)/mL | Standard Error 409 |
p-value: 0.991t-test, 2 sided
Primary
Change in Plasma Concentration of DHPG From Baseline
The change in DHPG will be compared between atomoxetine responders and non-responders.
Time frame: 18 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Change in Plasma Concentration of DHPG From Baseline | Responders | -0.059 ng/mL | Standard Deviation 0.074 |
| Atomoxetine HCl (Strattera) | Change in Plasma Concentration of DHPG From Baseline | Non-responders | -0.081 ng/mL | Standard Deviation 0.14 |
p-value: 0.652t-test, 2 sided
Primary
Change in Plasma Concentration of DHPG From Baseline
The change in DHPG will be compared between atomoxetine responders and non-responders.
Time frame: 6 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Change in Plasma Concentration of DHPG From Baseline | Responders | 0.031 ng/mL | Standard Deviation 0.18 |
| Atomoxetine HCl (Strattera) | Change in Plasma Concentration of DHPG From Baseline | Non-Responders | -0.066 ng/mL | Standard Deviation 0.157 |
p-value: 0.13t-test, 2 sided
Primary
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.
Time frame: 6 weeks
Population: Participants who completed 6 week milestone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Responders | 554.2 ng/mL | Standard Error 63.5 |
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Non-Responders | 501.7 ng/mL | Standard Error 61.4 |
p-value: 0.558t-test, 2 sided
Primary
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.
Time frame: Baseline (first dose)
Population: 6-week and 18-week responder classifications have different sample sizes, as there are 2 milestones within this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Responder at 6 weeks | 268.5 ng/mL | Standard Deviation 117.2 |
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Non-Responder at 6 weeks | 220.4 ng/mL | Standard Deviation 76 |
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Responder at 18 weeks | 247.8 ng/mL | Standard Deviation 128.7 |
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Non-Responder at 18 weeks | 216.2 ng/mL | Standard Deviation 77.3 |
Comparison: Comparing 6-week responders and 6-week non-respondersp-value: 0.197t-test, 2 sided
Comparison: Comparing 18-week responders and 18-week non-respondersp-value: 0.562t-test, 2 sided
Primary
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.
Time frame: 18 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Responders | 601.3 ng/mL | Standard Error 88.2 |
| Atomoxetine HCl (Strattera) | Maximum Plasma Concentration (Cmax) of Atomoxetine | Non-Responders | 375.5 ng/mL | Standard Error 120.2 |
p-value: 0.147t-test, 2 sided
Primary
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).
Time frame: 6 weeks
Population: Individuals who completed 6 week milestone
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Atomoxetine HCl (Strattera) | Number of Participants Classified as Responders and Non-responders to Intervention | Responders | 14 Participants |
| Atomoxetine HCl (Strattera) | Number of Participants Classified as Responders and Non-responders to Intervention | Non-Responders | 15 Participants |
Primary
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).
Time frame: 18 weeks
Population: Participants who completed 18 week milestone
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Atomoxetine HCl (Strattera) | Number of Participants Classified as Responders and Non-responders to Intervention | Responder | 13 Participants |
| Atomoxetine HCl (Strattera) | Number of Participants Classified as Responders and Non-responders to Intervention | Non-Responder | 7 Participants |
Primary
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.
Time frame: Baseline
Population: 6-week and 18-week responder classifications have different sample sizes, as there are 2 milestones within this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Responder at 6 weeks | 0.363 ng/mL | Standard Deviation 0.164 |
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Non-responder at 6 weeks | 0.412 ng/mL | Standard Deviation 0.178 |
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Responder at 18 weeks | 0.382 ng/mL | Standard Deviation 0.177 |
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Non-responder at 18 weeks | 0.363 ng/mL | Standard Deviation 0.184 |
Comparison: Comparing 6-week responders and 6-week non-respondersp-value: 0.456t-test, 2 sided
Comparison: Comparing 18-week responders and 18-week non-respondersp-value: 0.822t-test, 2 sided
Primary
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.
Time frame: 6 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Responders | 0.395 ng/mL | Standard Deviation 0.15 |
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Non-Responders | 0.345 ng/mL | Standard Deviation 0.125 |
p-value: 0.343t-test, 2 sided
Primary
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.
Time frame: 18 weeks
Population: The overall participants were classified into 2 groups based on responder status.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Responders | 0.323 ng/mL | Standard Deviation 0.14 |
| Atomoxetine HCl (Strattera) | Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG) | Non-responders | 0.283 ng/mL | Standard Deviation 0.139 |
p-value: 0.539t-test, 2 sided