Introduction
Attention deficit hyperactivity disorder (ADHD) has a reported
prevalence of between 3-5% in children and adults, and is more common
in males than females1,2. Typical symptoms include
inattention, hyperactivity and impulsivity 3. A number
of young patients will continue to have symptoms as adults, although
studies have shown that a proportion of patients diagnosed as adults did
not have ADHD as children / adolescents4. Treatment
with stimulants (primarily methylphenidate and amphetamine) is
recommended as first-line therapy when medical treatment is indicated in
children (over 6 years of age), adolescents and
adults2. Stimulants affect the central nervous system
by blocking presynaptic noradrenaline and dopamine reuptake in neuronal
synapses. Atomoxetine is a second-line treatment alternative that acts
primarily as a selective presynaptic noradrenaline-reuptake inhibitor,
without a direct effect on presynaptic dopamine
reuptake5. Microdialysis measurement in rats has shown
increased extracellular levels of noradrenalin and dopamine in the
prefrontal cortex in response to atomoxetine, but unaltered dopamine
levels in the striatum and nucleus accumbens6. The
result is that atomoxetine does not have the same abuse liability as the
stimulants methylphenidate and amphetamine. Atomoxetine is recommended
for ADHD-patients for whom stimulants are contraindicated or who have
experienced significant adverse effects when using stimulants. However,
cardiovascular adverse effects, including raised blood pressure and
tachycardia may also occur when using atomoxetine7.
Atomoxetine is metabolized to two metabolites – 4-hydroxyatomoxetine
(and further to 4‑hydroxyatomoxetine-O-glucuronide) and, to a lesser
degree, N -desmethylatomoxetine5. Although
4‑hydroxyatomoxetine exhibits potent inhibition of noradrenaline
reuptake (as potent as atomoxetine itself), it is present in only small
amounts (up to 1 % of the atomoxetine concentration) and, therefore,
has only a minor contribution to the therapeutic effect of atomoxetine.N -desmethylatomoxetine is also unlikely to have an impact on
treatment effect due to lower activity than the parent compound. Factors
determining the metabolism and concentration levels of the parent
compound are therefore crucial in determining response to atomoxetine
treatment. The metabolism of atomoxetine to 4‑hydroxyatomoxetine is
catalysed primarily by the cytochrome P450-enzyme CYP2D6, while the
metabolism of atomoxetine to N -desmethylatomoxetine is catalysed
by CYP2C198. Both CYP2D6 and CYP2C19 are highly
polymorphic enzymes. Identification of genetic variants with increased,
reduced or no enzymatic activity has been described. Among Caucasians,
about 7% and 3-4% of the population, respectively, have variants with
the CYP2D6 and CYP2C19 poor metabolizer (PM) genotype, while 1‑2% and
4% have the CYP2D6 and CYP2C19 ultra-rapid (UM) genotype, respectively.
Following metabolism, atomoxetine is primarily excreted in urine as
glucuronidated metabolites8.
Studies of atomoxetine pharmacokinetics have shown a significant
association with CYP2D6 activity, finding a 5-time increase in maximum
serum concentration (Cmax) and a 10-time increase in
cumulative serum concentration (area under the curve, AUC), increased
total body clearance and extended elimination half-life (t ½) in
patients having the CYP2D6 PM phenotype compared to normal metabolizers
(NM)9,10. Similar effects of CYP2D6-phenotype were
also observed in children and adolescents (7-14 years of
age)11. Patients with PM phenotype may therefore have
higher atomoxetine levels and a higher risk of adverse effects, since
many adverse effects are dose dependent. Care is therefore advised when
dosing atomoxetine in this patient group. The Clinical Pharmacogenetics
Implementation Consortium (CPIC) have summarized
treatment-recommendations for both children and adults according to
CYP2D6 phenotype in international guidelines12.
However, pre-emptive CYP2D6 genotyping of patients starting
atomoxetine is still not implemented in clinical practice. Data
regarding the effect of CYP2C19 genotype on atomoxetine
metabolism, concentration and effect is more limited, although one study
found an association between serum concentration and CYP2C19genotype in Asian patients13.
The aim of the present study was to investigate the added effects ofCYP2C19 genotypes on atomoxetine concentration in patients with
known CYP2D6 genotype using therapeutic drug monitoring (TDM)
data.