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Atomoxetine

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Atomoxetine
Clinical data
Trade namesStrattera
Other names(R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
AHFS/Drugs.comMonograph
MedlinePlusa603013
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63 to 94%[2][3][4]
Protein binding98%[2][3][4]
MetabolismHepatic, via CYP2D6[2][3][4]
Elimination half-life5.2 hours[2][3][4]
ExcretionRenal (80%) and faecal (17%)[2][3][4]
Identifiers
  • (3R)-N-Methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.120.306 Edit this at Wikidata
Chemical and physical data
FormulaC17H21NO
Molar mass255.36 g/mol
291.81 g/mol (hydrochloride) g·mol−1
3D model (JSmol)
  • CC1=C(C=CC=C1)O[C@H](CCNC)C2=CC=CC=C2
  • InChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1 checkY
  • Key:VHGCDTVCOLNTBX-QGZVFWFLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Atomoxetine (brand name: Strattera) is a norepinephrine (noradrenaline) reuptake inhibitor which is approved for the treatment of attention deficit hyperactivity disorder (ADHD).[5] As of 2017 it is available as a generic medication in the United States.[6]

Medical uses

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults.[5] However, its efficacy has not been studied in children under six years old.[3] Its primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential.[3] While it has been shown to significantly reduce inattentive and hyperactive symptoms, the responses were lower than the response to stimulants. Additionally, 40% of participants who were treated with atomoxetine experienced significant residual ADHD symptoms.[7]

The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent.[2] A further 2–4 weeks may be required for the full therapeutic effects to be seen.[8] Its efficacy may be less than that of stimulant medications.[9]

Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant discontinuation effects being seen.[3]

Contraindications

Contraindications include:[3]

  • Hypersensitivity to atomoxetine or any of the excipients in the product
  • Symptomatic cardiovascular disease including:
-moderate to severe hypertension
-atrial fibrillation
-atrial flutter
-ventricular tachycardia
-ventricular fibrillation
-ventricular flutter
-advanced arteriosclerosis

Side effects

Incidence of adverse effects:[3][4][10][11]

Very common (>10% incidence) adverse effects include:

  • Nausea (26%)
  • Xerostomia (Dry mouth) (20%)
  • Appetite loss (16%)
  • Insomnia (15%)
  • Fatigue (10%)
  • Headache
  • Cough

Common (1-10% incidence) adverse effects include:

  • Constipation (8%)
  • Dizziness (8%)
  • Erectile dysfunction (8%)
  • Somnolence (sleepiness) (8%)
  • Abdominal pain (7%)
  • Urinary hesitation (6%)
  • Tachycardia (high heart rate) (5-10%)
  • Hypertension (high blood pressure) (5-10%)
  • Irritability (5%)
  • Abnormal dreams (4%)
  • Dyspepsia (4%)
  • Ejaculation disorder (4%)
  • Hyperhidrosis (abnormally increased sweating) (4%)
  • Vomiting (4%)
  • Hot flashes (3%)
  • Paraesthesia (sensation of tingling, tickling, etc.) (3%)
  • Menstrual disorder (3%)
  • Weight loss (2%)
  • Depression
  • Sinus headache
  • Dermatitis
  • Mood swings

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects including

The FDA of the US has issued a black box warning for suicidal behaviour/ideation.[4] Similar warnings have been issued in Australia.[3][13] Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.[3]

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.[3] The most common symptoms of overdose include:[3]

  • Gastrointestinal symptoms
  • Somnolence
  • Dizziness
  • Tremor
  • Abnormal behaviour
  • Hyperactivity
  • Agitation
  • Dry mouth
  • Tachycardia
  • Hypertension
  • Mydriasis

Less common symptoms:[3]

The recommended treatment for atomoxetine overdose includes use of activated charcoal to prevent further absorption of the drug.[3]

Pharmacology

Pharmacodynamics

Atomoxetine inhibits the presynaptic norepinephrine transporter, preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter expression is minimal.[14] In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.[15] In mice, atomoxetine was also found to increase prefrontal catecholamine levels without affecting striatal or accumbal levels.[16]

Atomoxetine's status as a SERT inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural norepinephrine and serotonin transporters, respectively.[17] However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment.[15][16]

Atomoxetine has been found to act as an NMDA antagonist in rat cortical neurons, with an IC50 of 3.47 µM.[18][19] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[18][19] Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α1 receptor antagonists, but could be potentiated by NMDA or an α2 receptor antagonist, suggesting a glutamatergic mechanism.[20] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.[21] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.[22][23]

Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. It inhibited Kir3.1/3.2, Kir3.2, and Kir3.1/3.4 currents, with IC50s of 10.9, 12.4, and 6.5 μM, respectively.[24] Kir3.1/3.2 ion channels are stimulated by M2, α2, D2, and A1 stimulation and stimulation of other Gi-coupled receptors.[24] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[24] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

4-hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors.[25] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

Binding profile of atomoxetine and its metabolites[26][15][25][27][14][28]
Protein Ki (nM) for atomoxetine Ki (nM) for 4-hydroxyatomoxetine Ki (nM) for N-desmethylatomoxetine
SERT 77 43 ?
5-HT1A >1,000 ? ?
5-HT1B >1,000 ? ?
5-HT1D >1,000 ? ?
5-HT2 2,000 1,000 1,700
5-HT6 >1,000 ? ?
5-HT7 >1,000 ? ?
NET 5 3 92
α1 11,400 20,000 19,600
α2A 29,800 >30,000 >10,000
β1 18,000 56,100 32,100
M1 >100,000 >100,000 >100,000
M2 >100,000 >100,000 >100,000
DAT 1451 ? ?
D1 >10,000 >10,000 >10,000
D2 >10,000 >10,000 >10,000
H1 12,100 >100,000 >100,000
GABAA 200 >30,000 >10,000
NMDA 3,470a ? ?
δOR ? 300 ?
κOR ? 95 ?
μOR ? 422 ?
σ1 >1,000 ? ?
Kir3.1/3.2 10,900b ? ?
Kir3.2 12,400b ? ?
Kir3.1/3.4 6,500b ? ?
hERG 6,300 20,000 5,710

All values are for human receptors unless otherwise specified. arat cortex bXenopus oocytes

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.[14] Hepatic first-pass metabolism is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.[14] Maximum plasma concentration is reached in 1-2 hours.[14] If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 1 hour.[14] Drugs affecting gastric pH have no effect on oral bioavailability.[29]

Atomoxetine has a volume of distribution of 0.85 L/kg, with limited partitioning into red blood cells.[14]</ref> It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%).[14]</ref>[28] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.[14]</ref>

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.[14][30] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.[30]</ref>

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhbition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6-17 μmol/L.[14]</ref> Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.[29]

Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolizers, with >96% and 80% of a total dose being excreted in urine, respectively.[14] The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers.[14] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.[14]

Major metabolites of atomoxetine in humans.[14]

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher AUCs and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[14]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.[14]

Interactions

Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.[31][32][33]

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia[34][32] QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.[32]

Other notable drug interactions include:[3]

Chemistry and composition

Atomoxetine, or methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine, has a molecular weight of 255.36, and is supplied as a white, granular powder along with pregelatinized starch and dimethicone.[5] The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.[5]

Atomoxetine is soluble up to 27.8 mg/mL in water.[5]

  • Strattera 60-mg capsule back
    Strattera 60-mg capsule back
  • Strattera 60-mg capsule front with Lilly logo
    Strattera 60-mg capsule front with Lilly logo

Synthesis

Detection in biological fluids

Atomoxetine may be quantitated in plasma, serum or whole blood in order to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.[35]

History

Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current U.S. patent owner. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the FDA in 2002 for the treatment of ADHD. It is under patent until 2017.[36] On May 30, 2017 the FDA approved the generic production by four pharmaceutical companies.[37] On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market.[38] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[39] In a 29 July 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."[40]

Brand names

In India, atomoxetine is sold under brand names including Attentrol [Sun Pharma], Axepta, [Intas Pharma] Attera [Icon pharma], Tomoxetin [Torrent Pharma], Atokem [Alkem Pharma], and Attentin [Ranbaxy Pharma].

In Romania, atomoxetine is sold under the brand name Strattera.

In Iran, atomoxetine is sold under brand names including stramox by TeKaJe Co.

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.[41][42][43]

See also

  • Orphenadrine (modified base and similar termination of the molecule) it is a variant of the same structure
  • Fluoxetine (modified base and same termination of the molecule)

References

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