Atomoxetine

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Abstract
Atomoxetine was generally well tolerated in clinical trials; withdrawal rates due to adverse events in atomoxetine-treated versus placebo-treated patients participating in the two major trials were 7.8% versus 4.3% and 9.3% versus 2.4% (p < 0.05 for the latter trial). Adverse events reported significantly more frequently with atomoxetine than placebo included dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems and palpitations. Modest increases in heart rate and blood pressure were well tolerated and gradually decreased on cessation of treatment. Atomoxetine was not associated with QT interval prolongation. Atomoxetine can be administered once or twice daily. Its subjective-effects profile is different to that of methylphenidate and atomoxetine is not associated with abuse or diversion; it is therefore not a controlled substance in the US. This also means repeat prescriptions during long-term treatment can be more conveniently processed. Conclusion: Atomoxetine is an effective and generally well tolerated treatment for adults with ADHD. It is a nonstimulant and is the first ADHD treatment to be approved specifically for adult use based on its efficacy in well controlled adult trials. It can be administered as a single daily dose or split into two evenly divided doses. It carries negligible risk of abuse or diversion and is not a controlled substance. Atomoxetine is a valuable new treatment option for adults with ADHD and is particularly useful in patients who are at risk for substance abuse or who do not wish to take a controlled substance. Atomoxetine has demonstrated selective inhibition of the presynaptic uptake of norepinephrine in adrenergic neurons in animals. A study in humans showed marked inhibition of norepinephrine uptake (p = 0.054 vs placebo). Atomoxetine demonstrated selectivity as serotonin uptake into platelets isolated from study participants was unaffected. In the prefrontal cortex of the rat brain, atomoxetine increased extracellular levels of norepinephrine and dopamine (but not serotonin) and in the subcortical areas it increased extracellular norepinephrine but not dopamine. Increased norepinephrine transmission in these areas may play a role in the efficacy of atomoxetine in ADHD and may indicate the potential for the alleviation of symptoms of comorbid depression and anxiety by atomoxetine. The lack of increase in dopamine transmission in the subcortical areas may indicate a low potential for atomoxetine to produce tics, have psychomimetic effects or lead to abuse. Atomoxetine had no appreciable affinity for various neurotransmitter receptors in the rat or human brain, suggesting that it has a low potential for adverse effects and/or drug interactions. There were modest increases in heart rate and systolic blood pressure (BP) and no QT interval prolongation in atomoxetine recipients in the pivotal trials. Small but statistically significant increases from baseline in heart rate, BP and bodyweight were observed during the 34-week extension phase. The subjective-effects profile of atomoxetine is distinct from that of methyl-phenidate. Atomoxetine was rated significantly higher than placebo for ‘bad’ and ‘sick’ effects, which indicates that it is unlikely to be associated with abuse. Methylphenidate was rated higher than placebo for stimulant effects and dysphoric or psychomimetic effects. Atomoxetine is rapidly absorbed from the gastrointestinal tract after oral administration and has an absolute bioavailability of 94% in PMs and 63% in EMs. The median time to reach maximum plasma concentrations (Cmax) at steady state was approximately 1–2 hours in both groups. Food slowed the rate, but not the extent, of absorption of atomoxetine and the drug can be administered with or without food. At steady state, Cmax for atomoxetine was almost 6-fold higher in PMs than in EMs and mean area under the plasma concentration-time curve was approximately 8-fold higher. The steady-state volume of distribution of atomoxetine after intravenous administration is 0.85 L/kg and is similar for PMs and EMs. The apparent volume of distribution was 1.02 L/kg in PMs and 2.33 L/kg in EMs. At therapeutic concentrations, 98% of atomoxetine is bound to plasma protein (principally to albumin). The same metabolites of atomoxetine are formed (4-hydroxyatomoxetine and N-desmethylatomoxetine) regardless of CYP2D6 status, but the proportions of circulating metabolites differ according to the metabolic status of individuals. In EMs, atomoxetine and 4-hydroxyatomoxetine (equipotent with atomoxetine for norepinephrine transporter inhibition) are the principal circulating compounds. Because in PMs the rate of formation of 4-hydroxyatomoxetine is slower, the principal circulating compounds are atomoxetine and N-desmethylatomoxetine (a relatively inactive metabolite). The exposure of PMs to atomoxetine is, however, approximately 8- to 10-fold that of EMs, which is primarily due to the slower rate of formation of 4-hydroxyatomoxetine, but also the reduced overall rate of plasma clearance of atomoxetine. Plasma elimination half-life (t½) of atomoxetine in PMs is approximately 4-fold longer than in EMs (20 vs 5 hours) indicating increased systemic exposure to atomoxetine in PMs. The mean apparent plasma clearance of atomoxetine at steady state was approximately 0.036 L/h/kg for PMs versus 0.373 L/h/kg for EMs. Atomoxetine is eliminated from the body mainly via excretion of its glucuronidated metabolites in the urine (>80%) with approximately 13–22% and 1–2% eliminated in the faeces of PMs and EMs, respectively. Less than 3% is eliminated as unchanged drug. Although Cmax of atomoxetine was not increased in patients with hepatic impairment, there was increased systemic exposure in that population due to decreased atomoxetine clearance, necessitating...