Atomoxetine PBPK-PD Clinical Study
Condition: ADHD
Study type: Observational

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.
    

Intervention name(s): Atomoxetine Hydrochloride
Intervention type(s): Drug
Intervention description(s): Atomoxetine dose adjusted to achieve pre-defined concentration
Intervention MeSH terms: Atomoxetine Hydrochloride
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.