Clinical trial NCT03154359: Atomoxetine PBPK-PD Clinical Study
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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: ADHD
Lead sponsor: Children's Mercy Hospital Kansas City
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2017-05-16
Enrollment: 51
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Males and females 6-18 years of age, with a diagnosis of ADHD.

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.

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

Primary outcomes:
measure: Number of Participants Classified as Responders and Non-responders to Intervention
timeFrame: 6 weeks
measure: Number of Participants Classified as Responders and Non-responders to Intervention
timeFrame: 18 weeks
measure: Maximum Plasma Concentration (Cmax) of Atomoxetine
timeFrame: Baseline (first dose)
measure: Maximum Plasma Concentration (Cmax) of Atomoxetine
timeFrame: 6 weeks
measure: Maximum Plasma Concentration (Cmax) of Atomoxetine
timeFrame: 18 weeks
measure: Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine
timeFrame: Baseline (first dose)
measure: Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine
timeFrame: 6 weeks
measure: Area Under the Plasma Concentration-time Curve (AUC) of Atomoxetine
timeFrame: 18 weeks
measure: Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG)
timeFrame: Baseline
measure: Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG)
timeFrame: 6 weeks
measure: Plasma Concentration of 3,4-dihydroxyphenylglycol (DHPG)
timeFrame: 18 weeks
measure: Change in Plasma Concentration of DHPG From Baseline
timeFrame: 6 weeks
measure: Change in Plasma Concentration of DHPG From Baseline
timeFrame: 18 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: James S Leeder, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Gaedigk A, Ndjountche L, Divakaran K, Dianne Bradford L, Zineh I, Oberlander TF, Brousseau DC, McCarver DG, Johnson JA, Alander SW, Wayne Riggs K, Steven Leeder J. Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events. Clin Pharmacol Ther. 2007 Feb;81(2):242-51. doi: 10.1038/sj.clpt.6100033.
citation: Gaedigk A, Jaime LK, Bertino JS Jr, Berard A, Pratt VM, Bradfordand LD, Leeder JS. Identification of Novel CYP2D7-2D6 Hybrids: Non-Functional and Functional Variants. Front Pharmacol. 2010 Oct 4;1:121. doi: 10.3389/fphar.2010.00121. eCollection 2010.
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