Atomoxetine

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),^[19] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.^[19][18][20] In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.^{[49][50][51][52]}

Nocturnal enuresis

Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication.^{[53][54][55][56]}

Excessive sleepiness

Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy.^{[57][58][59][60][61]}

Traumatic brain injury

Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI).^[62][63] It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition,^[64] lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome.^[62] A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.^[65] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.^[63][66]

Absorption

The absorption of atomoxetine with oral administration is rapid and complete.^{[11][3][5][2]} The drug's absolute bioavailability is 63 to 94%.^[11][2] This is moderated by first-pass metabolism and CYP2D6 status, with poor metabolizers having a bioavailability of 94% and extensive metabolizers having a bioavailability of 63%.^[11][2] Extensive metabolizers are considered to have normal CYP2D6 activity and constitute >90% of people, while poor metabolizers constitute a small minority of up to 7%.^{[11][69][3][2]} The bioavailability of atomoxetine is not different between capsule and solution forms.^[5]

The time to peak levels of atomoxetine is 1 to 2 hours.^[2][3] It has been reported that the time to peak levels was 1.0 hours in CYP2D6 extensive metabolizers and 2.5 hours in CYP2D6 poor metabolizers.^[5] Taking atomoxetine with food does not affect its bioavailability or total exposure but decreases peak levels by 9% with a typical meal and 37% with a standard high-fat breakfast.^[11][2] In addition, food delays the time to peak levels by 3 hours.^[11][2] Atomoxetine exposure increases proportionally with higher doses over a range of 10 to 120 mg orally.^[3][11][5] Exposure to atomoxetine is proportional to body weight, and hence weight-normalizing dosing is required to produce equivalent exposure.^[11][5]

In CYP2D6 poor metabolizers, atomoxetine peak levels are 5- to 6-fold higher and total exposure is 8- to 10-fold higher than in CYP2D6 extensive metabolizers.^{[2][14][5][12]} Similarly, in Asian adults homozygous for the hypoactive CYP2D6*10 allele, atomoxetine peak levels were about 1.5-fold higher and total exposure 2-fold higher compared to extensive metabolizers.^[11][5][12] There is little accumulation of atomoxetine with repeated administration in CYP2D6 extensive metabolizers, but significant accumulation in CYP2D6 poor metabolizers.^[11][12] The pharmacokinetics of atomoxetine, for instance elimination half-life, volume of distribution, and clearance, are similar with a single dose versus at steady state.^[3]

Distribution

Atomoxetine is well-distributed and its volume of distribution is 0.85 to 1.02 L/kg in CYP2D6 extensive metabolizers and 2.25 L/kg in CYP2D6 poor metabolizers, with its distribution being equivalent to total body water.^{[11][3][14][2]} Atomoxetine and its metabolites show only limited partitioning into red blood cells.^[11] Atomoxetine crosses the blood–brain barrier, with this appearing to be due primarily to passive diffusion rather than active transport.^[5] The drug is not a substrate of P-glycoprotein.^[5] Animal studies have found that atomoxetine and/or its metabolites can cross the placenta, but fetal exposure was substantially lower than maternal exposure.^[11] Similarly, only a small amount of atomoxetine and/or metabolites were excreted in milk in animals.^[11]

Atomoxetine shows high plasma protein binding of 98.7% and is primarily bound to albumin and to a lesser extent to α₁-acid glycoprotein and immunoglobulin G (IgG).^{[11][3][5][2][90]} Atomoxetine's limitedly active metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, whereas its active metabolite 4-hydroxyatomoxetine shows plasma protein binding of 66.6%, which is substantially less than that of atomoxetine itself.^[11][5]

Metabolism

Atomoxetine is primarily metabolized via oxidative metabolism.^[11][2] The three major metabolic pathways include aromatic ring hydroxylation mainly by CYP2D6 but also other cytochrome P450 enzymes into 4-hydroxyatomoxetine, benzylic hydroxylation by an unspecified enzyme into 2-hydroxymethylatomoxetine, and N-demethylation by CYP2C19 into N-desmethylatomoxetine.^[11][5][12] In addition, N-desmethylatomoxetine undergoes hydroxylation by CYP2D6 into N-desmethyl-4-hydroxyatomoxetine.^[11] The hydroxylated metabolites of atomoxetine undergo glucuronidation via UDP-glucuronyltransferase (UGT) enzymes to form glucuronide conjugates.^[11][5][2]

As previously described, first-pass metabolism of atomoxetine is substantially greater, bioavailability is lower, peak levels and total exposure are much greater, and elimination half-life is much longer in CYP2D6 poor metabolizers than in extensive metabolizers.^[2][11][12] The overall metabolism of atomoxetine is similar regardless of CYP2D6 status.^[11][3][14] In addition, 4-hydroxyatomoxetine remains the major metabolite of atomoxetine independently of CYP2D6 status.^[11][3] But the quantitative amounts of formed atomoxetine metabolites and their rates of formation are substantially different depending on CYP2D6 status.^[11][14] Studies with radiolabeled atomoxetine have shown that peak levels of radioactivity are essentially the same between CYP2D6 extensive metabolizers and CYP2D6 poor metabolizers.^[11] However, total exposure of radioactivity was larger and elimination half-life of radioactivity was longer (62 hours vs. 18 hours) in CYP2D6 poor metabolizers versus CYP2D6 extensive metabolizers.^[11] Circulating 4-hydroxyatomoxetine levels are about 1% of those of circulating atomoxetine levels in CYP2D6 extensive metabolizers and about 0.1% of those of circulating atomoxetine levels in CYP2D6 poor metabolizers.^[2][3][5] Similarly, N-desmethylatomoxetine circulates at much lower levels than atomoxetine, about 5% of those of atomoxetine in CYP2D6 extensive metabolizers and 45% of those of atomoxetine in CYP2D6 poor metabolizers.^[2][3][5]

4-Hydroxyatomoxetine shows similar affinity for the norepinephrine transporter (NET) as atomoxetine but much higher affinity for the serotonin transporter (SERT) in comparison (with SERT affinity ~14-fold lower than NET affinity), whereas N-desmethylatomoxetine shows much lower affinity for the monoamine transporters (MATs) than atomoxetine and 4-hydroxyatomoxetine (with NET affinity ~20-fold lower than that of atomoxetine).^{[11][3][5][90]} Despite differences in atomoxetine metabolism, CYP2D6 status has been said in literature reviews to not affect the overall tolerability and safety of atomoxetine.^[11][69][5] However, poor metabolizers did show greater heart rate increase (+9.4–11 bpm vs. +5.0–7.5 bpm), blood pressure increase (4.21 mm Hg vs. 2.13 mm Hg systolic and 2.75 mg Hg vs. 2.40 mm Hg diastolic), and more weight loss (–1.2 kg vs. +0.8 mg) than extensive metabolizers.^{[2][11][5][12]} In addition, various side effects, including insomnia, sedation, weight loss, constipation, dry mouth, erectile dysfunction, excessive sweating, and urinary retention, among others, have been found to be around twice as frequent in poor metabolizers relative to extensive metabolizers.^{[2][69][5][12]} The same was true for discontinuation rates (11.2% vs. 6.3%).^[2] In terms of dosage adjustment for CYP2D6 poor metabolizers or those taking strong CYP2D6 inhibitors, the Food and Drug Administration (FDA) label says that this may be necessary and provides directions for this,^[2] whereas literature reviews state that it is not considered necessary based on clinical trial experience.^[11][3]

Elimination

Atomoxetine and its metabolites are eliminated mainly via excretion into urine.^[11] Less than 3% of atomoxetine is excreted unchanged in urine regardless of CYP2D6 status, indicating extensive metabolism.^{[2][11][3][15]} In CYP2D6 extensive metabolizers, who are considered to have normal CYP2D6 activity, more than 96% of a dose of radiolabeled atomoxetine is excreted in urine within 24 hours and 1 to 2% is excreted in feces.^{[11][14][15][5]} Conversely, in CYP2D6 poor metabolizers, excretion is slower, with only 27% excreted after 24 hours, a majority of radioactivity excreted within 72 hours, and ~144 hours required for full excretion.^[11][15][5] In addition, only 80% of radioactivity is excreted in urine while 13 to 22% is excreted in feces in CYP2D6 poor metabolizers.^[11][14] The major excreted metabolite of atomoxetine is 4-hydroxyatomoxetine glucuronide, which accounts for >80% of the dose in urine but <17% of the dose in feces.^[2][3] The fractions excreted in urine as 4-hydroxyatomoxetine and 4-hydroxyatomoxetine glucuronide account for 86% of a dose in CYP2D6 extensive metabolizers, but only 40% in CYP2D6 poor metabolizers.^[11] CYP2D6 poor metabolizers excrete greater amounts of minor atomoxetine metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates, than extensive metabolizers.^[11]

The elimination half-life of atomoxetine is 4.5 to 5.3 hours in CYP2D6 extensive metabolizers.^[2][12][13] However, in CYP2D6 poor metabolizers, the half-life of atomoxetine is 19 to 21.6 hours, or about 4-fold longer in comparison.^{[2][14][12][13]} In CYP2D6 extensive metabolizers, the half-lives of 4-hydroxyatomoxetine and N-desmethylatomoxetine are similar at around 6 to 8 hours, whereas in CYP2D6 poor metabolizers, the half-life of N-desmethylatomoxetine is much longer at around 33 to 40 hours.^[2][11][13] Atomoxetine levels in cerebrospinal fluid (CSF) with atomoxetine at a dosage of 80 mg/day were 6.6 ng/mL at 8 hours post-dose and 1.4 ng/mL at 24 hours post-dose following 2 weeks of administration.^[5]