Atomoxetine PBPK-PD Clinical Study

August 1, 2023 updated by: Steve Leeder, Children's Mercy Hospital Kansas City

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
51

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital and Clinics

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

2 years to 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Males and females 6-18 years of age, with a diagnosis of ADHD.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of Participants Classified as Responders and Non-responders to Intervention
Time Frame: 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").
6 weeks
Number of Participants Classified as Responders and Non-responders to Intervention
Time Frame: 18 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").
18 weeks
Maximum Plasma Concentration (Cmax) of Atomoxetine
Time Frame: 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.
Baseline (first dose)
Maximum Plasma Concentration (Cmax) of Atomoxetine
Time Frame: 6 weeks
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
Time Frame: 18 weeks
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
Time Frame: 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.
Baseline (first dose)
Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine
Time Frame: 6 weeks
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
Time Frame: 18 weeks
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)
Time Frame: 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.
Baseline
Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG)
Time Frame: 6 weeks
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)
Time Frame: 18 weeks
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
Time Frame: 6 weeks
The change in DHPG will be compared between atomoxetine responders and non-responders.
6 weeks
Change in Plasma Concentration of DHPG From Baseline
Time Frame: 18 weeks
The change in DHPG will be compared between atomoxetine responders and non-responders.
18 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Children's Mercy Hospital Kansas City

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: James S Leeder, PharmD, PhD, Children's Mercy Hospital Kansas City

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 12, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 16, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 4, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 12, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 16, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 8, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 1, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 16100728
  • U54HD090258-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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