The Pharmacology and Toxicology of Atomoxetine

 

Jennifer Audi, MD, Stephen Traub, MD, Michael J. Burns, MD

Authors' affiliation:
Division of Toxicology
Department of Emergency Medicine
Beth Israel Deaconess Medical Center
One Deaconess Road, CCW-2
Boston, MA   02215
Phone: (617) 754-2326
Fax: (617) 754-2350

Corresponding authors email:
jaudi@caregroup.harvard.edu
mburns@caregroup.harvard.edu
straub@bidmc.harvard.edu

Int J Med Toxicol 2004; 7(1): 6


There are no financial, litigation, or other relationships that may lead to a conflict of interest, particularly with Lilly, manufacturer of atomoxetine (StratteraTM).

This manuscript has not been published elsewhere nor submitted for publication elsewhere.

Introduction
Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity and affects between 2 and 20 percent of the general population.(1) Currently, the first-line treatment for ADHD is psychostimulant medications such as such as methylphenidate, dextroamphetamine, and amphetamine mixtures.(2-5) Thirty to fifty percent of children and adults with ADHD, however, either do not tolerate or do not respond to stimulants.(2,6) These drugs are further limited by their ability to cause mood swings, propensity for abuse, and short duration of therapeutic effects (4 to 12 hours). (2)

Concern about the tolerability and abuse liability of psychostimulants has led to interest in the development of drugs for ADHD with a different mechanism of action. Until recently, non-psychostimulant medications (e.g., tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), buproprion and clonidine) used to treat ADHD have been limited by variable efficacy and a narrower margin of safety when compared to the approved stimulant medications. (4-6) In March 2003, atomoxetine became the newest non-psychostimulant drug to be approved by the FDA for the treatment of ADHD. (7,8) To date, atomoxetine has demonstrated similar efficacy as compared to methylphenidate and amphetamine mixtures and has been associated with only minor side effects. (2-8) Atomoxetine may be dosed once daily, which is likely to improve patient compliance.(2-4)

Structure & Pharmacology
Atomoxetine hydrochloride (LY139603, (?)-N-methyl-gamma-(2-methylphenoxy) benzene propanamine hydrochloride) is currently marketed in the United States as StratteraTM by Eli Lilly & Company.(7-11) It is structurally similar to the antidepressants, fluoxetine, reboxetine, and viloxazine (Figure 1).(12) Atomoxetine is a relatively potent and selective inhibitor of norepinephrine (NE) reuptake (NRI).(5,6,9,10) It binds with high affinity to the pre-synaptic NE transporter but has little affinity for monoamine receptors or other central nervous system (CNS) neurotransmitter receptors or transporters. (5,6,9,10) Based on in vitro data, atomoxetine is two to three orders of magnitude more effective in the inhibition of NE uptake (Ki 1.9 nM) than in the inhibition of either dopamine (DA)[(Ki 1600 nM] or serotonin (5-HT) [Ki 750 nM] uptake. (5,9,10) Atomoxetine is over three orders of magnitude more effective in the inhibition of NE uptake than in the binding to alpha1- and alpha2-adrenergic, H1-histaminergic, and M1-muscarinic, and numerous other CNS receptors (binding at micromolar concentrations). (5,9,10) Since NE transporters also transport DA nonselectively, atomoxetine may enhance dopaminergic tone in brain regions rich in this neurotransmitter.(13,14) In animal studies, atomoxetine binds the NE transporter at a site different from that of cocaine.(10,15,16,17)

The efficacy of atomoxetine and psychostimulants in treating ADHD is likely related to enhancement of cortical NE and DA neurotransmission in the prefrontal cortex (PFC), a region involved with attention and memory. Enhancement of cortical NE neurotransmission is also likely why atomoxetine can decrease the signs and symptoms of depression similar to other NE reuptake blockers (e.g., TCAs and reboxetine). (10,15,16,17)

Atomoxetine, unlike stimulants, is not associated with adverse motor effects such as tics, psychostimulant effects, or significant abuse potential. (5,13,14) It is postulated that a lack of NE transporters in the striatum and nucleus accumbens (brain regions involved in movement and psychotomimetic effects, respectively) means that atomoxetine does not increase DA concentrations in these areas. (5,13,14) For instance, in animals, atomoxetine increases extracellular levels of NE and DA in the PFC but not the striatum or nucleus accumbens in rats transfected with human neuronal transporters.(5) In addition, atomoxetine does not substitute appreciably for cocaine or methamphetamine in drug discrimination studies in monkeys. (18)

Atomoxetine has little affinity for sodium, potassium, and calcium channels and, consequently, has not been shown to have any significant effect on cardiac conduction in pre-marketing studies. (5,9,10) Atomoxetine therapy is not associated with PR, QRS, or QTc prolongation or cardiac dysrhythmias. (6,11,16,17) At therapeutic doses, atomoxetine is associated with mild increases in heart rate and blood pressure that plateau during treatment. (6,11,17) As compared to placebo, treatment with atomoxetine is associated with a mean increase of approximately 2 mm Hg in diastolic blood pressure, 2 mm Hg in systolic blood pressure, and 7 beats per minute in pulse. (6,11,17) Increases are dose-dependent and related to the ability to metabolize the drug.(11) Although the magnitude of effects are small, atomoxetine-treated patients (adult and pediatric) have a higher frequency of tachycardia (3 versus 0.8%), high systolic (1.9 versus 1.2%) and diastolic (0.8 versus 0.4%) blood pressure measurements, and orthostatic hypotension (1.8 versus 0.5%) as compared to placebo-treated patients. (6,11,17)

Pharmacokinetics
Atomoxetine hydrochloride is formulated as 10, 18, 25, 40, and 60 mg capsules for oral administration.(11) It is well-absorbed from the gastrointestinal (GI) tract, with a bioavailability that ranges from 63 to 94 percent.(11) Peak plasma concentrations (Cmax) range from 1200 to 1500 ng/mL and occur from 1 to 3 hours post ingestion.(10,11,19) Although the manufacturer states that atomoxetine can be taken with or without food, food can decrease the rate and extent of absorption (delay and decrease in Cmax by 3 hours and 9 to 37%, respectively).(10,11,19,20) Steady-state plasma concentrations range from 37 to 76 ng/mL.(10,17) At therapeutic concentrations, atomoxetine is extensively protein-bound (98 percent), primarily to albumin.(10,11) The steady-state volume of distribution (Vd) is 0.85 L/kg.(10,11,19,20)

Atomoxetine is metabolized in the liver by the cytochrome P450 mixed function oxidase system, predominantly by the CYP2D6 isoenzyme. (11,19,20) Metabolism of atomoxetine has a bimodal distribution (two distinct populations) due to genetic polymorphism of the CYP2D6 isoenzyme. (11,19) A minority of patients (approximately 7 percent of Caucasians, 2 percent of African Americans, and less than 1 percent of Asians) have reduced activity of the CYP2D6 enzyme system and are considered poor metabolizers (PM). (11) PM have an approximately 10-fold greater area under the curve (AUC), 5-fold higher peak plasma concentration, and a 4-fold slower elimination (plasma half-life of about 20 hours) for atomoxetine as compared to extensive metabolizers (EM), who are people with normal CYP2D6 activity (plasma half-life of about 5 hours). (11,19,21) In EM subjects, the majority of a dose of atomoxetine is excreted within 24 hours as compared to 72 hours in PM subjects. (11,20,21)  The rate at which atomoxetine undergoes biotransformation to its primary oxidative metabolite, 4-hydroxyatomoxetine, is what differentiates PM from EM.(19)

Atomoxetine undergoes phase I hydroxylation to 4-hydroxyatomoxetine and phase II glucuronidation to 4-hydroxyatomoxetine-O-glucuronide. This moiety is then excreted in the urine (over 80 percent) or feces (less than 17 percent).(11,20,21) Less than 3 percent of a dose of atomoxetine is excreted unchanged in the urine.(11) In PM subjects, atomoxetine phase I hydroxylation to 4-hydroxyatomoxetine occurs primarily from the CYP2C19 isoenzyme.(11,19-21) Repeated administration of atomoxetine is not associated with a significant induction of the CYP2D6 isoenzyme (no auto-induction).(11) Atomoxetine does not appreciably inhibit any CYP P450 isoenzymes.(11)

Atomoxetine should be initiated at a dose of 40 mg in adults and those greater than 70 kg body weight or 0.5 mg/kg for those children and adolescents less than 70 kg.(11) After a minimum of 3 days, the total daily dose may be increased to 80 mg or 1.2 mg/kg body weight.(11) The maximum total daily dose should not exceed 100 mg or 1.4 mg/kg body weight since higher doses do not enhance efficacy.(11) The daily dose may be administered as a single dose or divided evenly in the morning and evening.(2,3,11,22)

No other significant gender or ethnic differences in the pharmacokinetics of atomoxetine have been reported.(11) The pharmacokinetics of atomoxetine in children (greater than 6 years old) and adolescents are similar to those in adults.(11) In premarketing trials, the pharmacokinetics of atomoxetine were studied in over 400 children (less than 6 years old) and adolescents.(2,3,6,11)  The pharmacokinetics of atomoxetine have not been evaluated in elderly patients.(11) Although PM patients may initially experience a slightly higher rate of minor side effects as compared to EM subjects, dose adjustments are not recommended by the manufacturer for PMs since these effects are not clinically significant.(11) Patients with moderate to severe liver disease (Child-Pugh Classes B and C) have significant reductions in atomoxetine clearance as compared to normal controls.(11,23) The manufacturer recommends that initial doses should be reduced to 25 and 50 percent of the normal dose for patients with severe and moderate hepatic impairment, respectively.(11) No dosage adjustment is required for patients with renal impairment.(11) Data is not available with respect to the use of atomoxetine and pregnant or lactating women.(11) Atomoxetine is classified as Pregnancy Category C.

Drug Interactions
Concurrent use of CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) will likely prolong metabolism of atomoxetine. In one study of 22 healthy EM individuals, co-administration of paroxetine with atomoxetine increased the Cmax, AUC, and elimination t1/2 of atomoxetine significantly; the resultant pharmacokinetic profile was similar to that observed in PM subjects.(24) Dosage adjustment may be necessary when atomoxetine is co-administered with CYP2D6 inhibitors to EM subjects.

Although atomoxetine binds to albumin in the plasma, it has not been shown to alter the binding of other drugs (e.g., warfarin, phenytoin) to albumin.(11) Drugs that alter gastric pH (e.g., magnesium hydroxide, omeprazole) do not effect the bioavailability of atomoxetine.(11) To date, no clinically significant pharmacokinetic drug-food interactions have been observed with atomoxetine.(11) 

Based on its pharmacologic activity as a NRI, atomoxetine might potentiate the effects of other sympathomimetic agents. Although not studied, the manufacturer states that atomoxetine should not be administered with a MAOI or within two weeks of taking a MAOI.(11) Although no warning or contraindication is listed with respect to other sympathomimetics, there is potential for a serious interaction if atomoxetine were combined with other drugs that increase synaptic NE concentrations (e.g., TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), cocaine, amphetamines, phenylpropanolamine, pseudoephedrine, phenylephrine, dopamine).(11) As atomoxetine does not potentiate serotonergic neurotransmission, it should not precipitate the serotonin syndrome when combined with agents that increase CNS serotonin levels. The co-administration of methylphenidate with atomoxetine has not been shown to increase the cardiovascular effects beyond those seen with methylphenidate alone.(11,25)

Clinical Efficacy
Although atomoxetine was first investigated as an antidepressant in the early 1980s, it is currently indicated only for the treatment of ADHD. (7,8,16,17) Several, large, randomized studies have shown atomoxetine to be superior to placebo for the treatment of ADHD.(22,26-29) Only one randomized, open label study compared methylphenidate with atomoxetine in children with ADHD.(30) Atomoxetine provided therapeutic effects comparable to those of methylphenidate, with similar safety and tolerability. Similar results were found in small sub-group analyses of prior studies.(2) The results of this study were limited by several confounding factors.(30) The study was open-label rather than being blinded, groups were not truly randomized and not well-matched demographically, and a large number of study participants withdrew from the study prior to its completion.

Although initial efficacy data appear promising, additional prospective, randomized, blinded studies need to be performed to confirm that atomoxetine is as effective as stimulant medications and that its efficacy is maintained with long-term use for ADHD.

Toxicology/Adverse Effects
Animal Toxicity Data.
Minimal animal toxicity data is available from the manufacturer. In dogs, atomoxetine had little effect on the cardiac conduction system (doses given unknown). (17) Young rats tolerated gavage doses of 50 mg/kg/day without effect on learning, memory, fertility, or reproductive performance.(11) No adverse fetal effects were demonstrated when pregnant rats were treated with up to 150 mg/kg/day by gavage.(10) When pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage, slight maternal toxicity and a decrease in live fetuses was noted.(11)

Human Toxicity Data. In premarketing trials, 2337 children, adolescents, and adults were treated with atomoxetine. (6,11) In both short- and long-term (up to 1 year) trials, atomoxetine has well-tolerated; few serious adverse effects and no deaths have been associated with the drug. (6,11) Adverse events that have occurred in at least 5 percent of atomoxetine-treated patients (all age groups) at a rate at least twice that of placebo-treated patients include dyspepsia, nausea, vomiting, decreased appetite, dizziness, and weight loss. (6,11) In children and adolescents, there were also significant increases in the incidence of fatigue and mood swings in atomoxetine-treated patients as compared to placebo-treated patients. (6,11) In adults, there were significant increases in the incidence of dry mouth, constipation, insomnia, decreased libido, ejaculatory problems, impotence, dysmenorrhea, and urinary hesitancy or retention as compared to placebo-treated patients. (6,11) In premarketing trials, discontinuation of atomoxetine by patients due to adverse events was not significantly different from placebo (3.8 versus 1.4 percent, respectively). (6,11) Although the incidence of drug discontinuation and reporting of adverse events by EM and PM subjects was similar, PM subjects had a slightly higher increase in pulse rate and lost more weight that EM subjects. (6,11) No significant laboratory or electrocardiographic abnormalities were noted during atomoxetine premarketing trials. (6,11) In addition, there was no evidence of a withdrawal syndrome upon atomoxetine discontinuation.(11) The safety of atomoxetine has not been studied in children less than 6 and adults over 65 years old.(11)

Overdose. During preclinical trials, no large overdoses of atomoxetine were reported.(11) At twice the recommended daily dose, atomoxetine was associated with anorexia, dyspepsia, abdominal pain, and increased heart rate. There were no changes in blood pressure or in the QTc interval on the electrocardiogram.(11) Subsequent to market release, there have been a small number of acute and chronic overdoses reported in both children and adults.(31) The largest acute overdose, 1080 mg in a 16-year old male, and largest chronic overdose, 4.4 mg/kg/day for 26 consecutive days in a child, were associated with full recovery.(31) The most commonly reported signs and symptoms following overdose were moderate somnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinal effects.(31) Other than somnolence, the toxic effects are largely an exaggeration of the drug's known pharmacological effects and are consistent with sympathetic nervous system stimulation. Although overdose data is largely nonexistent, other effects that might be expected include tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis, tremulousness, anxiety, agitation, and seizures. Significant muscular activity might result in rhabdomyolysis.

The specificity of atomoxetine for NE reuptake inhibition is so great that, even following overdose, it is highly unlikely that atomoxetine would obtain concentrations in plasma necessary to bind to and produce effects at other CNS receptors (micromolar inhibitory constants). (5,9,10)

Overdose Management
Treatment of patients with atomoxetine overdose is supportive. Gastrointestinal decontamination, consisting of a single dose of activated charcoal, should be initiated as soon as possible after patient presentation and stabilization. Based on pharmacokinetic data, multi-dose charcoal, hemodialysis, hemoperfusion, are not likely to be effective in enhancing atomoxetine elimination. Nonspecific sedation and sympatholysis with benzodiazepines is recommended for those patients with moderate to severe agitation, tachycardia, or hypertension. 

Conclusion
Atomoxetine, a selective norepinephrine reuptake inhibitor, is a promising new drug in the treatment of attention deficit hyperactivity disorder. Early studies suggest that it is as effective as methylphenidate and superior to placebo for the control of symptoms of ADHD. (13,22,26-30) Atomoxetine appears to be a safe and well-tolerated drug with a low potential for abuse.(18,25) Early overdose data suggest that toxicity will consist of sympathomimetic effects. Patients that are poor metabolizers of CYP 2D6 substrates and those using drugs or foods that reduce CYP 2D6 activity are at greater theoretical risk for toxic effects. The combination of atomoxetine with other sympathomimetic agents may produce synergistic hyperadrenergic effects and should be avoided.  Additional studies in both humans and animals are needed to further define efficacy and toxicity.

References

  1. Swanson JM, Sergeant JA, Taylor E, et al. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 1998;351:429-433.
  2. Spencer T, Biederman J, Wilens TE, et al. Novel treatments for attention deficit/hyperactivity disorder in children. J Clin Psychiatry. 2002; 63(S12): 16-22.

  3. Spencer T, Biederman J, Wilens TE, et al. Overview and neurobiology of attention deficit/hyperactivity disorder. J Clin Psychiatry. 2002; 63(S12): 3-9.
  4. Wender EH. Managing stimulant medication for attention deficit/ hyperactivity disorder: an update. Pediatrics in Review. 2002; 23(7): 234-6.
  5. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002; 27(5): 699-711.
  6. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children with ADHD. J Clin Psychiatry. 2002; 63(S12): 50-55.
  7. Strattera approved to treat ADHD. FDA Consum 2003;37(2)4.
  8. Abramowicz M, Ed. Atomoxetine (Strattera) for ADHD. Med Letters Drugs Therap 2003; 45(1149)11-12.
  9. Wong DT, Threlkeld PG, Best KL, Bymaster FP. A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther 1982;222(1):61-65.
  10. Preti A. Tomoxetine (Eli Lilly & Co). Curr Opin Investig Drugs 2002;3(2):272-7.
  11. StratteraTM (atomoxetine HCl) package insert / prescribing information. Eli Lilly and Company, 3/2003; 1-16 (www.stratttera.com). 4/03
  12. Atomoxetine chemical structure. www.usp.org 4/03
  13. Stahl SM. Neurotransmission of cognition, part 1 dopamine is a hitchhike in frontal cortex: norepinephrine transporters regulate dopamine. J Clin Psychiatry 2003;64(1):4-5.
  14. Stahl SM. Neurotransmission of cognition, part 2 selective NRIs are smart drugs: exploiting regionally selective actions on both dopamine and norepinephrine to enhance cognition. J Clin Psychiatry 2003;64(2):110-111.
  15. Fowler JS, Ding YS, Volkow ND, et al. PET studies of cocaine inhibition of myocardial norepinephrine uptake. Synapse 1994;16(4):312-317.
  16. Chouinard G, Annable L, Bradwejn. An early phase II clinical trial of tomoxetine (LY 139603) in the treatment of newly depressed patients. Psychopharmacology 1984;83:126-128.
  17. Zerbe RL, Rowe H, Enas GG, et al. Clinical pharmacology of tomoxetine, a potential antidepressant. J Pharmacol Exp Ther 1985;232(1):139-143.
  18. Tidey JW, Bergman J. Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs. J Pharmacol Exp Ther 1998;285(3):1163-1174.
  19. Sauer JM, Ponsler GD, et al. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos 2003; 31(1): 98-107.
  20. Mattiuz EL, Ponsler GD, et al. Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the Fischer 344 rat and beagle dog. Drug Metab Dispos. 2003; 31(1): 88-97.
  21. Ring BJ, Gillespie JS, et al. Identification of the human cytochromes p450 responsible for atomoxetine metabolism. Drug Metab Dispos 2002; 30(3): 319-23.
  22. Michelson D, Allen AJ, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit/hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002; 159(11): 1896-901.
  23. Chalon SA, Desager JP, Desante KA, et al. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Ther 2003;73(3):178-191.
  24. Belle DJ, Ernest CS, et al. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol 2002; 42(11): 1219-27.
  25. Heil SH, Holmes HW, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 2002; 67(2): 149-56.
  26. Biederman J, Heiligenstein JH, et al. Efficacy on atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics 2002; 110(6): e75.
  27. Michelson D, Faries D, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose response study. Pediatrics 2001; 108(5): e83.
  28. Spencer T, Biederman J, et al. Overview and neurobiology of attention deficit/hyperactivity disorder. J Clin Psychiatry 2002; 63(S12): 3-9.
  29. Spencer T, Heiligenstein JH, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention deficit/hyperactivity disorder. J Clin Psychiatry 2002; 63(12): 1140-47.
  30. Kratochvil CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 2002;41(7):776-784.
  31. 31. Personal communication. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, June 2003


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