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.