Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Psychoanaleptics, centrally acting sympathomimetics
ATC code: N06BA09
Mechanism of action and Pharmacodynamic effects
Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter, its presumed mechanism of action, without directly affecting the serotonin or dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. Atomoxetine has two major oxidative metabolites: 4- hydroxyatomoxetine and N-desmethylatomoxetine. 4- Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the noradrenaline transporter but unlike atomoxetine, this metabolite also exerts some inhibitory activity at the serotonin transporter. However, any effect on this transporter is likely to be minimal as the majority of 4-hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower concentrations (1% of atomoxetine concentration in extensive metabolisers and 0.1% of atomoxetine concentration in poor metabolisers).

N-Desmethylatomoxetine has substantially less pharmacological activity compared with atomoxetine. It circulates in plasma at lower concentrations in extensive metabolisers and at comparable concentrations to the parent drug in poor metabolisers at steady state.
Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In a randomised, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties.

Clinical efficacy and safety
Paediatric population
Atomoxetine has been studied in trials in over 5000 children and adolescents with ADHD. The acute efficacy of atomoxetine in the treatment of ADHD was initially established in six randomised, double-blind, placebo-controlled trials of six to nine weeks duration. Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for atomoxetine treated and placebo treated patients. In each of the six trials, atomoxetine was statistically significantly superior to placebo in reducing ADHD signs and symptoms.
Additionally, the efficacy of atomoxetine in maintaining symptom response was demonstrated in a 1 year, placebo-controlled trial with over 400 children and adolescents, primarily conducted in Europe (approximately 3 months of open label acute treatment followed by 9 months of double-blind, placebo- controlled maintenance treatment). The proportion of patients relapsing after 1 year was 18.7% and 31.4% (atomoxetine and placebo, respectively). After 1 year of atomoxetine treatment, patients who continued atomoxetine for 6 additional months were less likely to relapse or to experience partial symptom return compared with patients who discontinued active treatment and switched to placebo (2% vs. 12% respectively). For children and adolescents periodic assessment of the value of ongoing treatment during long-term treatment should be performed.
Atomoxetine was effective as a single daily dose and as a divided dose administered in the morning, and late afternoon/early evening. Atomoxetine administered once daily demonstrated statistically significantly greater reduction in severity of ADHD symptoms compared with placebo as judged by teachers and parents.

Active Comparator Studies
In a randomised, double-blind, parallel group, 6 week paediatric study to test the non- inferiority of atomoxetine to a standard extended-release methylphenidate comparator, the comparator was shown to be associated with superior response rates compared to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and the comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p=0.016). However, this study excluded patients who were stimulant nonresponders.

Adult population
Atomoxetine has been studied in trials in over 4800 adults who met DSM-IV diagnostic criteria for ADHD. The acute efficacy of atomoxetine in the treatment of adults was established in six randomised, double-blind, placebo-controlled trials of ten to sixteen weeks’ duration. Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for atomoxetine treated and placebo treated patients. In each of the six trials, atomoxetine was statistically significantly superior to placebo in reducing ADHD signs and symptoms (Table X).
Atomoxetine-treated patients had statistically significantly greater improvements in clinical global impression of severity (CGI-S) at endpoint compared to placebo- treated patients in all of the 6 acute studies, and statistically significantly greater improvements in ADHD- related functioning in all 3 of the acute studies in which this was assessed (Table X). Long-term efficacy was confirmed in 2 six-month placebo controlled studies, but not demonstrated in a third (Table X).
Table X          Mean Changes in Efficacy Measures for Placebo-Controlled Studies
Changes from Baseline in Patients with at Least One Postbaseline
Value (LOCF)
CAARS-Inv:SV
CGI-S                AAQoL or AISRSa
N    Mean                  Mean                   Mean
Study      Treatment                         p-value                p-value              p-value Change                Change                 Change
Acute Studies
LYAA ATX                    133        -9.5        0.006        -0.8       0.011          -            - PBO                134        -6.0                     -0.4
LYAO ATX                    124       -10.5        0.002        -0.9       0.002          -            - PBO                124        -6.7                     -0.5
LYBY ATX                     72       -13.6        0.007        -1.0       0.048          -            - PBO                 75        -8.3                     -0.7
LYDQ ATX                    171        -8.7       <0.001        -0.8       0.022        14.9         0.030 PBO                158        -5.6                     -0.6                    11.1 LYDZ     ATX                192       -10.7       <0.001        -1.1       <0.001       15.8         0.005 PBO                198        -7.2                     -0.7                    11.0 LYEE     ATX                191       -14.3       <0.001        -1.3       <0.001       12.83        <0.001 PBO                 195       -8.8                      -0.8                    8.20 Long-Term Studies
LYBV ATX                    185        -11.6       0.412         -1.0      0.173       13.90         0.045 PBO                109        -11.5                     -0.9                  11.18 LYCU ATX                    214        -13.2       0.005         -1.2      0.001       13.14         0.004 PBO                216        -10.2                     -0.9                   8.62 LYCW ATX                    113        -14.3      <0.001         -1.2      <0.001         -            - PBO                120         -8.3                     -0.7

Abbreviations: AAQoL = Adult ADHD Quality of Life Total Score; AISRS = Adult ADHD Investigator Symptom Rating Scale Total Score; ATX = atomoxetine; CAARS- Inv:SV = Conners Adult ADHD Rating Scale, Investigator Rated, screening version Total ADHD Symptom Score; CGI-S = Clinical Global Impression of Severity; LOCF = last observation carried forward; PBO = placebo.
a ADHD symptom scales; results shown for Study LYBY are for AISRS; results for all others are for CAARS-Inv:SV.

In sensitivity analyses using a baseline-observation-carried-forward method for patients with no postbaseline measure (i.e. all patients treated), results were consistent with results shown in Table X.
In analyses of clinically meaningful response in all 6 acute and both successful long- term studies, using a variety of a priori and post hoc definitions, atomoxetine-treated patients consistently had statistically significantly higher rates of response than placebo-treated patients (Table Y).
Table Y       Number (n) and Percent of Patients Meeting Criteria for Response in Pooled Placebo-Controlled Studies
Response Defined by                Response Defined by
Improvement of at least 1           40% Improvement on point on CGI-S               CAARS-Inv:SVat Endpoint
Group           Treatment       N        n (%)        p-value      N         n (%)      p-value a
Pooled Acute Studies
640         401         <0.001      841         347       <0.001
ATX    652       (62.7%)                   851       (41.3%)
PBO                283                                 215
(43.4%)                             (25.3%)
Pooled Long-Term
Studiesa
758          482          <0.001        663          292       <0.001 ATX      611        (63.6%)                      557        (44.0%)
PBO                   301                                     175
(49.3%)                                 (31.4%) aIncludes all studies in Table X except: Acute CGI-S response analysis excludes 2 studies in patients with comorbid disorders (LYBY, LYDQ); Acute CAARS response analysis excludes 1 study in which the CAARS was not administered (LYBY).

In two of the acute studies, patients with ADHD and comorbid alcoholism or social anxiety disorder were studied and in both studies ADHD symptoms were improved.
In the study with comorbid alcohol abuse, there were no differences between atomoxetine and placebo with respect to alcohol use behaviours. In the study with co-morbid anxiety, the comorbid condition of anxiety did not deteriorate with atomoxetine treatment.
The efficacy of atomoxetine in maintaining symptom response was demonstrated in a study where after an initial active treatment period of 24 weeks, patients who met criteria for clinically meaningful response (as defined by improvement on both CAARS-Inv:SV and CGI-S scores) were randomized to receive atomoxetine or placebo for an additional 6 months of double-blind treatment. Higher proportions of atomoxetine-treated patients than placebo- treated patients met criteria for maintaining clinically meaningful response at the end of 6 months (64.3% vs. 50.0%; p=0.001). Atomoxetine-treated patients demonstrated statistically significantly better maintenance of functioning than placebo-treated patients as shown by lesser mean change on the Adult ADHD Quality of Life (AAQoL) total score at the 3-month interval (p=0.003) and at the 6-month interval (p=0.002).

QT/QTc study
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metabolizer (PM) subjects dosed up to 60 mg of atomoxetine BID, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was a slight increase in QTc interval with increased atomoxetine concentration.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under 6 years of age.

Pharmacokinetic studies have shown that atomoxetine capsules and oral solution are bioequivalent.

Absorption: Atomoxetine is rapidly and almost completely absorbed after oral administration, reaching mean maximal observed plasma concentration (Cmax) approximately 1 to 2 hours after dosing. The absolute bioavailability of atomoxetine following oral administration ranged from 63% to 94% depending upon inter- individual differences in the modest first pass metabolism. Atomoxetine can be administered with or without food.

Distribution: Atomoxetine is widely distributed and is extensively (98%) bound to plasma proteins, primarily albumin.

Biotransformation: Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Individuals with reduced activity of this pathway (poor metabolisers) represent about 7% of the Caucasian population and, have higher plasma concentrations of atomoxetine compared with people with normal activity (extensive metabolisers). For poor metabolisers, AUC of atomoxetine is approximately 10-fold greater and Css, max is about 5- fold greater than extensive metabolisers. The major oxidative metabolite formed is 4- hydroxyatomoxetine that is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine but circulates in plasma at much lower concentrations.
Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine does not inhibit or induce CYP2D6 at therapeutic doses.
Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

Elimination: The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers.
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.
Linearity/non-linearity: pharmacokinetics of atomoxetine are linear over the range of doses studied in both extensive and poor metabolisers.

Special populations
Hepatic impairment results in a reduced atomoxetine clearance, increased atomoxetine exposure (AUC increased 2-fold in moderate impairment and 4-fold in severe impairment), and a prolonged half-life of parent drug compared to healthy controls with the same CYP2D6 extensive metaboliser genotype. In patients with moderate to severe hepatic impairment (Child Pugh Class B and C) initial and target doses should be adjusted (see section 4.2).
Atomoxetine mean plasma concentrations for end stage renal disease (ESRD) subjects were generally higher than the mean for healthy control subjects shown by Cmax (7% difference) and AUC0-∞ (about 65% difference) increases. After adjustment for body weight, the differences between the two groups are minimized.
Pharmacokinetics of atomoxetine and its metabolites in individuals with ESRD suggest that no dose adjustment would be necessary (see section 4.2).